Landscape of Lankacidin Biomimetic Synthesis: Structural Revisions and Biogenetic Implications

Article abstract of DOI:10.1021/acs.joc.0c01930

In this report, a unified biomimetic approach to all known macrocyclic lankacidins is presented. By taking advantage of the thermolysis of N,O-acetal to generate the requisite N-acyl-1-azahexatriene species, we eventually realized the biomimetic Mannich macrocyclization, from which all of the macrocyclic lankacidins can be conquered by orchestrated desilylation. The reassignments of the reported structures of isolankacidinol (7 to 10) and the discovery of a recently isolated lankacyclinol found to be in fact 2,18-bis-epi-lankacyclinol (72) unraveled the previously underappreciated chemical diversity exhibited by the enzymatic macrocyclization. In addition, the facile elimination/decarboxylation/protonation process for the depletion of C1 under basic conditions resembling a physiological environment may implicate more undiscovered natural products with variable C2/C18 stereochemistries (i.e., 62, 73, and 75). The notable aspect provided by a biomimetic strategy is significantly reducing the step count compared with the two previous entries to macrocyclic lankacidins.

Full text of DOI:10.1021/acs.joc.0c01930

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Article
The Landscape of Lankacidin Biomimetic Synthesis:
Structural Revisions and Biogenetic Implications
Kuan Zheng, Defeng Shen, Bingbing Zhang, and Ran Hong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01930 • Publication Date (Web): 28 Sep 2020
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Page 1 of 19
The Journal of Organic Chemistry
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The Landscape of Lankacidin Biomimetic Synthesis: Structural
Revisions and Biogenetic Implications
8
9
Kuan Zheng1, Defeng Shen1, Bingbing Zhang1,2 and Ran Hong1,*
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1 CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China;
2 University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
Me
iPr
Lankacidin antibiotics
I
OTBS
Me
lankacidin C
(bundlin A, T-2636 C)
lankacidin A
O
TBSO
O
N
CHO
Me
HN
OMe
Me
O
O
18
(bundlin B, sedecamycin)
2-6
steps
Bu3Sn
HN
Me
4
Me
7
6 steps
lankacidinol
lankacidinol A
(T-2636 F)
(T-2636 D)
S
N
2
TBSO
5
O
O
lankacyclinol
(T-2636 G)
EtO2C
SO2
OMe
13
lankacyclinol A
(T-2636 E)
TBSO
OTBDPS
Bn
O
O
N
O
isolankacidinol
O
(revised)
2,18-bis-epi-lankacyclinol
(revised, novel family member)
Me
the synthetic precursor for
biomimetic Mannich macrocyclization
TBSO
Me
Me
Me
O
ABSTRACT: In this report, a unified biomimetic approach to all known macrocyclic lankacidins was presented. By taking
advantage of the thermolysis of N,O-acetal to generate the requisite N-acyl-1-azahexatriene species, we eventually realized the
biomimetic Mannich macrocyclization, from which all of the macrocyclic lankacidins can be conquered by orchestrated
desilylation. The reassignments of the reported structures of isolankacidinol (7 to 10) and the discovery of a recently isolated
“lankacyclinol” found to be in fact 2,18-bis-epi-lankacyclinol (72), unraveled the previously underappreciated chemical diversity
exhibited by the enzymatic macrocyclization. In addition, the facile elimination/decarboxylation/protonation process for the
depletion of C1 under basic conditions resembling a physiological environment may implicate more undiscovered natural products
with variable C2/C18 stereochemistries (i.e., 62, 73, and 75). The notable aspect provided by a biomimetic strategy is significantly
reducing the step count compared with the two previous entries to macrocyclic lankacidins.
INTRODUCTION
Figure 1. Representative Lankacidin Antibiotics.
25
O
Me
HO
HN
Me
O
HO
Me
The preliminary reports of lankacidin antibiotics from
actinomycete strains date back over sixty years ago when the
Swiss and Japanese groups independently isolated a nitrogen-
containing crystalline lankacidin C (1) (Figure 1),1 also
referred to as bundlin A or T-2636 C.2 The complex structure
as well as absolute configuration of 1 and its coisolated
monoacetate lankacidin A (2) were established later by X-ray
crystallographic analysis of their hydrazone derivatives.3
During a period from 1971 to 1975, Harada and coworkers
reported several new members (3–7) from the broth cultures of
Streptomyces rochei var. volubilis,4 which share the parent 17-
membered macrocyclic framework endowed with two
pentadienyl alcohols and a bridged, fully substituted β-oxo-δ-
lactone with an amide residue adjacent to an all-carbon
quaternary center. Isolankacidinol (7) was postulated to be a
C5-epimer of lankacidinol (3) based upon a combination of a
1D NMR experiment and the negative Cotton effect observed
in the optical rotatory dispersion (ORD) spectrum of the
octahydrotriacetate derivative of 7.4d Lankacyclinol (5) and
congener 6, hypothetically derived from the enzymatic
eliminative decarboxylation (depleting C1), were also isolated
by the same team.4a,d In 2018, Wang and coworkers disclosed
2,18-seco-lankacidinol A (8) and B (9) from Streptomyces sp.
HS-NF-1178.5 The R-C4 stereochemistry of 9, the only
naturally
24
23
O
3
HN
18
O
O
O
O
HN
O
Me
20
Me
22
Me
Me
4
5
2
Me
Me
16
Me
19
O
Me
Me
6
1
O
O
14
10
RO
7
13
OH
RO
OH
RO
OH
8
21
Me
1
Me
Me
5
lankacidin C ( ) (R = H)
3
lankacyclinol ( ) (R = H)
lankacidinol ( ) (R = H)
(T-2636 F)
(bundlin A, T-2636 C)
(T-2636 G)
2
6
lankacidin A ( ) (R = Ac)
(bundlin B, sedecamycin)
4
lankacyclinol A ( ) (R = Ac)
lankacidinol A ( ) (R = Ac)
(T-2636 E)
(T-2636 D)
OH
HO
HN
Me
H
N
Me
OH
OH
O
O
O
O
O
O
Me
Me
Me
Me
Me
Me
Me
O
Me
Me
O
O
O
HO
OH
HO
OH
HO
OH
Me
2,18-seco-lankacidinol A (
reported structure (ref. 5)
Me
2,18-seco-lankacidinol B (
reported structure (ref. 5)
Me
isolankacidinol (
9
8
)
7
)
)
reported structure (ref. 4d)
revised
revised
revised
O
Me
HO
HN
Me
HN
O
OH
OH
OH
O
O
O
Me
Me
Me
Me
Me
Me
Me
O
Me
Me
O
O
O
O
HO
OH
OH
HO
HO
OH
12
Me
Me
Me
11 2,18-seco-lankacidinol B (
)
10
2,18-seco-lankacidinol A (
(ref. 6b)
)
isolankacidinol (
(this work)
)
(ref. 6a)
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occurring nonmacrocyclic lankacidin prior to our intermediates where the quaternary stereocenters were
established by convergent enolate acylation.18b,c By taking
advantage of the secured relay transformation of a stable
tricyclic carbamate to the natural product, Kende
accomplished the first total synthesis of lankacidin C (1) in
1993.19a This landmark achievement set the stage for the fully
synthetic entry to the target antibiotic family. Williams and
coworkers also reported their creative studies towards the
lactone segment, featuring a regio- and diastereoselective acyl
nitrene addition to dihydrofuran 22 to furnish cyclic
hemiacetal 23.20a A series of chemical manipulations provided
δ-lactone 24 with the C3–OH and the amido appendage
protected as carbamate. Although further elaboration of
segment 24 to the lankacidins was not fruitful,20b the
stereocontrolled -amido ester synthetic methodology
developed during the process has been successfully utilized by
the same laboratory to synthesize lankacyclinol (5), allowing
the C2 configuration to be established.20c
1
2
3
4
5
6
7
8
investigations, was reassigned to S-C4 (as shown in 12) by the
Seiple group through total synthesis later in the same year.6a
Very recently, the structure of 8 was also reassigned by us
through a modular approach to rule out the proposed C18–O
ether linkage in the original publication.6b
In addition to their structural complexity, lankacidins
possess an exceedingly broad array of biological activities.
Several congeners have showed strong antibacterial activities
against various gram-positive bacteria including multidrug
resistant clinical strains such as Staphylococcus aureus.7 The
mode of action was recently revealed through the inhibition of
protein synthesis by binding at the peptidyl transferase center
of the eubacterial large ribosomal subunit.8 Sedecamycin (the
generic name of 2) exhibited significant growth-inhibitory
potency against Treponema hyodysenteriae, and it was
approved in 1985 as a veterinary drug for the treatment of
swine dysentery (SD).9 Moreover, the same compound
displays a promising in vitro activity against the Trypanosoma
brucei parasite with an IC50 value of 33 µM, being 66-fold
more potent than eflornithine, a clinically used drug for late-
stage human African trypanosomiasis.10 Lankacidin C (1) was
recently identified as one of the top candidates to combat
Borrelia burgdorferi, thereby holding great promise for better
Lyme disease therapy.11 Additionally, modest to potent in vitro
and in vivo antitumor activities have been known for
decades.5,12 In 2016, mechanistic studies on the cytotoxic
action demonstrated that the lankacidin antibiotic is a novel
microtubule-stabilizing agent, which may target the paclitaxel
binding site.13
Current fermentation to produce lankacidins usually yields a
complex mixture of congeners. Moreover, available
semisynthetic modifications of the parent macrocycle were
severely limited due to its sensitivity to even mildly acidic or
basic conditions.4a,7c,14 Although a couple of analogs have been
prepared chemically or enzymatically,15 a de novo, practical
synthetic route to lankacidins would arguably enable access to
a greater diversity of small-molecule therapeutic leads with
improved pharmacological profiles.16 Herein, we described a
full account17 on the unified synthesis of all known
macrocyclic lankacidins in only 8–12 steps, permitting access
to a series of C2/C18 diastereomeric congeners as well as
revision of the reported structure of isolankacidinol (7). We
also uncovered that Wang’s lankacyclinol, exhibiting
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Previous Synthetic Approaches to the Lactonic
Core of the Lankacidin Antibiotics.
retro-Mannich
& hydrolysis
or retro-Prins
(C12-C13)
retro-Claisen
decarboxylation
or elimination
of C7-OR
HN
O
3
HN
O
OH
O
2
Me
2
Me
Me
Me
O
Me
O
acidic
conditions
basic
conditions
O
Me
14
O
'-amido--oxo-
-lactone core
13
A
Thomas
.
(1985, ref. 18a): 1,3-dipolar cycloaddition/methylation
LDA
HMPA
then MeI
O
NBn
O
NBn
Bn
O
H
H
toluene
reflux
N
18
Me
Et
2
Me
Et
Me
Et
Ph
Ph
Me
H
O
Ph
undesired C2
configuration
d.r. at C18
= 1:1.2
16
O
O
O
17
O
18
O
15
B
Kende Thomas
/ (ref. 18b,c, 19): enolate acylation/reduction/translactonization
.
Kende
(1993): first total synthesis of lankacidin C (34 LLS, 46 TS)
TBSO
O
19
1) LDA, then
TBDPSO
O
3
2) KEt3BH, –78 °C
3) TBAF, THF, rt
then MsOH
O
O
NH Me
SPy
18
Me
Me
Me
2
Me
N
O
PMBO
then Et3N, CDI
Me
18
2
I
3 steps, 61%
O
N
19
N
PMBO
I
O
TBS
O
20
21
C
Williams
Williams
.
(1999, ref. 20a): acyl nitrene insertion to dihydrofuran/hydrolysis
(2000): first total synthesis of lankacyclinol (25 LLS, 35 TS)
O
TBS
17 OH
EtO2CN3
then H2O
CO2Et
NH
O
5
O
O
NH Me
O
Me
Me
3
18
Me
2
3
18
h
cytotoxicity against human adenocarcinoma cells A549 (IC50
=
O
CO2Me
2
70%
Me
CO2Me
Me
O
O
Me
HO
24
(24 steps from L-malic acid)
Me
28 µg/mL), is actually a 2,18-bis-epimer of 5, a new natural
product.
O
22
23
We initially took note from the step-economy issue which
plagued all the previous strategies. Each route constructed the
β-oxo-δ-lactone core at a relatively early stage and invariably
reduced the C3 carbonyl group as a protected alcohol to
attenuate the sensitive nature of the intermediate. This not only
gives rise to a heteroatom-rich segment containing five
contiguous stereocenters, but also maximizes the extraneous
protecting-group and redox manipulations needed to access
the target, which in turn dramatically attenuated the synthetic
RESULTS AND DISCUSSION
Historical Context and Strategic Considerations. The
fascinating biological profile in conjunction with the synthetic
challenge has stimulated numerous synthetic efforts for more
than three decades.18-20 Representative approaches to construct
the lactone core prior to our own endeavor are summarized in
Scheme 1. Thomas’s early model studies involving 1,3-
dipolar cycloaddition followed by methylation provided
exclusively undesired C2 stereochemistry.18a Later, Thomas
and Kende independently devised a translactonization strategy
based on similar L-aspartic acid-derived -lactam
efficacy.21
A
fundamentally disparate skeleton-forming
strategy employed by the biosynthetic machinery of nature is
inspiring.22 In 2005, Arakawa and coworkers disclosed the
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The Journal of Organic Chemistry
isolation of acyclic δ-lactone LC-KA05 (27, Scheme 2A) and
confirmation of 27 as an essential biosynthetic intermediate.22c
They
1
2
3
4
5
A
HO
HN
Me
O
HO
HN
Me
O
ACP
Me
HO
O
Me
O
decarboxylated
PCP
S
S
5 6
, )
congeners (
6
7
8
9
enzymatic
Mannich-type
macrocyclization
amine
lkc
PKS
O
O
oxidase
O
O
HN
O
18
LkcG-TE
18
Me
Me
18
Me
Me
LkcE
Me
O
3
lankacidinol ( )
Me
2
2
Me
Me
4
lankacidinol A (
)
chain
release
NH
O
O
OH
O
FAD FADH2
OH
OH
RO
OH
R = Ac
RO
OH
HO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
C23-OH oxidized
1 2
Me
Me
29
Me
26
congeners (
, )
25
27
LC-KA05 (
)
28 R = H
LC-KA05-2 (
)
Me
B
C
O
1. n-Bu2BOTf (2 equiv)
DIPEA, ether, then
3-phenylpropanal
93%, d.r. 20:1
O
TBSO
Me
O
Me
TBSO
O
regioselective /
diastereoselective
macrocyclization
O
O
Bn
Bn
HN
OH
R
O
HN
N
N
18
Me
Me
Me
16
37
38
R = SO2Ph
R = OMe
Me
2
Me
Me Bn
2. (n-EtCO)2O, Et3N
DMAP, CH2Cl2
O
O
Me
O
O
31
Me
15
30
O
O
O
O
KHMDS, THF
2 steps, 58%
TBSO
OTBDPS
TBSO
OTBDPS
Me
Me
36
extremely
acid sensitive
prone to
Me
O
OTBS
Me
40
41
O
R = SO2Ph
R = OMe
Bu3Sn
R
retro-Mannich
H2N
O
O
O
+
Me
TBSO HN
OH
P
Me
42
OH
O
+
16 SnBu3
43
X-ray
O
Me
4
Me
I
EtO2C
O
O
NHBoc
18
34
I
(2 mol %)
iPr
Bn
O
15
13
OTBS
O
O
Me
Bn
Me
Me
Bn
5
O
9
O
NBoc
Ph
Ph
TBSO
Me
33
(2 equiv)
2
+
Me
O
+
+
N
N
O
TBSO
OTBDPS
O
32
O
Me Me
O
S
CH2Cl2, 23 °C, 20 min
> 90% nmr yield
12
8
BT
O
44
O
45
O
46
O
Me
39
mixture of 4 isomers
47
CCDC 1528201
35
Scheme 2. Biosynthesis Proposal (A), Initial feasibility Studies (B), and Retrosynthetic Analysis of Lankacidins (C).
also identified a multifunctional flavin-dependent amine
Retrosynthetic Analysis. The retrosynthetic disconnection
began with rupturing the critical C2–C18 bond of our primary
target lankacidinol (3) to afford a globally protected N-acyl
azahexatriene surrogate (i.e., 37 or 38)29 (Scheme 2C). We
anticipate the site-selective desilylations followed by C7-OH
acetylation or C24-OH oxidation on 36 after the
macrocyclization event will provide access to other
macrocyclic members of the family. In turn, formation of the
C15–C16 bond via Stille coupling would lead to advanced
vinyl iodide 39 and vinyl stannane (i.e., 40 or 41) with a
preinstalled N-lactoyl as well as a proper oxidation level at
C18. This synthetic design would not only provide a
playground for the Mannich macrocylization or intermolecular
model studies through facile alteration of different imine
surrogates, but also facilitate future synthetic studies toward
other acyclic lankacidin-related metabolites. Accordingly, 39
can be prepared from 44 by successive union of three building
blocks (45–47) of similar complexity. The classic carbonyl
group-based transformations and bond-forming sequence (i.e.,
C12–C13, ∆C8–C9, and then C4–C5) to construct 39 was
planned to formally emulate the previously proposed chain
elongation and termination steps in lankacidin biosynthesis.22c
oxidase (LkcE) responsible for the unusual amide oxidation of
27 at C18, followed by intramolecular C2-enolate trapping of
the resultant hypothetical iminium species to complete the
lankacidin macrocycle.
We envisaged a synthetic plan hinging on an unprecedented
late-stage
stereogenic
center-forming
Mannich
macrocyclization. While the Mannich reaction was well
adapted for the construction of five- to seven-membered ring
systems,23 cyclization leading to macrocycles were much less
explored.24 This circumstance was further exacerbated by the
elusive nature of critical diastereocontrol.25 Preliminary
feasibility studies were undertaken on truncated -ketolactone
32, which wassynthesized from 3-phenylpropanal in a 3-step
sequence (Scheme 2B).26 Subjection of 32 to an acid-
catalyzed Mannich reaction with N-Boc benzaldimine 3327
smoothly afforded a diastereomeric mixture of adducts 35 in
an 81% yield. Further investigations such as isomer separation
and N-Boc deprotection under a variety of conditions based on
this material proved difficult owing to its propensity to
undergo a retro-Mannich reaction.28 Such a process occurred
to neat 35 even during the prolonged storage at temperatures
below –20 °C. With these observations in mind, we
anticipated that a preinstallation of the O-silyl (S)-lactoyl
group in the macrocyclization precursor might avoid the
leverage of late-stage modification to the N-protecting group
within the strained, energetically unfavorable Mannich adduct.
Synthesis of the Truncated Azabutadiene Surrogate
Fragments. The preparation of the stannylated amido sulfone
40 from aldehyde 4230 and protected chiral lactamide 4331, at
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first a seemingly simple transformation, turned out to be a SI, Figure S1). Being cognizant of the reluctant
1
2
3
4
5
6
7
8
daunting challenge. As outlined in Scheme 3, the conventional
Brønsted acid32 and Lewis acid33 conditions utilizing
benzenesulfinic acid or its sodium salt only led to various side
transmetalation associated with the sterically congested
stannane might be the source of our frustrations,39a,b we
modified the structures of two Stille coupling partners.
Analogous results were observed using a desilylated vinyl
iodide 39a (entry 2). Also noteworthy is the fact that
replacement of 40 with 40a bearing a more reactive
trimethylvinyl stannyl moiety39c under otherwise identical
conditions (cat. [Pd(CH3CN)2Cl2], DMF, 23 °C) resulted in an
products
from
protodestannylation,
double
bond
isomerization, or desilylation of the starting materials.
Explorations based on nucleophilic trapping of the preformed
imine obtained via acylation of a N-metalloimine species were
also fruitless.34 Thus, an alternative route to initially access
N,O-acetal 41 was evaluated. Using Manolikakes’s protocol,35
43 was deprotonated with methylmagnesium chloride and
subsequently condensated with aldehyde 42 to generate labile
hemiaminal intermediate, which underwent acid-catalyzed
transacetalization in methanol to provide 41 (74% from 42) on
a decagram-scale. However, arylsulfinate displacement under
protonic acid conditions still occurred with extensive
destannylation, whereas heating 42 in aqueous sodium
arylsulfinate at 45 °C for 4 days only led to recycled starting
material. A mild indirect method inspired by Adamek’s work
was eventually adopted,36 in which treatment of N,O-acetal 41
increase of side product 49 (entry 3).
Although by
9
interchanging the tin and iodide substituents of two reaction
partners, an unstable product with the desired C15–C16
linkage could be isolated together with the recycled starting
materials, further spectroscopic elucidation precluded the
existence of an -amido sulfone structure (entry 4).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Attempts of Stille Coupling on Various Substrates.
Me
TBSO
Me
O
O
TBSO
OH
OH
O
with
triphenylphosphonium
tetrafluoroborate
gave
Me HN
R4
Me
HN
Me
Me
Me
O
R2
O
phosphonium salt 48 bearing a polar C–P+ bond after solvent
(including the coproduced methanol) removal under high
vacuum. Successive exposure of an ethanol-free chloroform
solution of this material to powdered sodium arylsulfinate
under sonication cleanly furnished -amido sulfone 40, which
was discovered to exert a pronounced tendency to undergo
destannylative sulfonyl migration to afford 49 upon contact
with silica gel or even during prolonged storage.37
R3
R4
Me
Pd(CH3CN)2Cl2
(20 mol%)
DMF, rt
R1
TBSO
O
O
Me
R1
TBSO
O
Me
imine fragment
R4
lactone fragment
entrya
result b
R2
R1
R3
--- c
---
---
---
---
---
---
1
2
39 TBDPS
39a
39 TBDPS
I
I
I
40
40
SnBu3 SO2Ph
SnBu3 SO2Ph
H
3
40a SnMe3 SO2Ph
40b
SO2Ph
Scheme 3. Various Approaches to Prepare Amido Sulfone 40.
4
39b TBDPS SnMe3
I
5
39 TBDPS
39 TBDPS
39 TBDPS
39 TBDPS
39c TBS
I
I
I
I
I
I
40c SnBu3 SPh
40d SnBu3 OH
1. MeMgCl, THF
–15 °C to rt
42,
then 15 h
TBSO
Me
O
O
6
Me
Me
7
48
41
41
41
SnBu3 PPh3BF4
CHO
+
H2N
Me HN
Bu3Sn
d
OTBS
8
SnBu3 OMe
SnBu3 OMe
SnBu3 OMe
38
: 45% (57%)
2. PPTs, MeOH
74%
42
43
Bu3Sn
OMe
9
---
---
41
10
39a
H
condition A
PhSO2Na, HCO2H
MeOH/H2O, rt
a
condition A
PhSO2H, CaCl2
CH2Cl2, rt
Unless otherwise indicated, reactions were performed with a lactone
fragment 39 (0.1 mmol) and imine fragment (0.2 mmol) in DMF (0.04 M).
Isolated yield. The coupling product not obtained. The reaction was
HBF4PPh3
(1 equiv)
CH2Cl2, then
evacuation at
5 mmHg
condition B
PhSO2H, MgSO4
CH2Cl2, rt
b
c
d
condition B
PhSO2Na, H2O
45 °C, 4 days
run at a 0.7 mmol scale with Pd2(dba)3 (20 mol%) and a 64% yield was
achieved based on recovered lactonic starting material.
condition C
PhSO2Na,TMSCl
CH3CN, rt
TBSO
Me
TBSO
HN
Me
O
TBSO
Me
Me
PhSO2Na
CHCl3, rt
Me HN
O
N,O-Acetal-based Mannich Chemistry Revisited:
A
PhO2S
N
O
sonication
54%
H
Bu3Sn
SO2Ph
BF4
Thermal Demethoxylation Approach. The enormous,
unexpected hurdle in synthesizing 37 via Stille cross-coupling
compelled us to abandon amido sulfone as the reaction
partner. A systematic evaluation of both reaction partners was
thus conducted. Relevant structural moieties including N,S-
acetal, hemiaminal, or phosphonium salt were found to be
incompatible with the coupling conditions (entries 5–7). It was
pleasing to discover that the coupling between N,O-acetal 41
and 39 successfully led to 38, which turned out to be acid-
liable but can be obtained in a 45% yield (entry 8).40 The
TBDPS protection of the C13 hydroxyl group proved to be
crucial because the coupling products from vinyl iodides
bearing TBS protection or no protection on the C13 position
were too sensitive to permit purification or characterization
(entries 9 and 10). Screening of further coupling conditions
PPh3
49
-amido sulfone
:
40
40
(from degradation of
)
48
phosphonium salt
Preparation
of
the
Precursor
for
Mannich
Macrocyclization: The Dead-End. With truncated imine
equivalent 40 in hand, we went further to construct the linear
precursor for the macrocyclization. Toward this end, the Stille
coupling of vinyl iodide 3938 with stannane 40 was explored in
the presence of bis(acetonitrile)dichloropalladium(II) (20
mol%) (Table 1, entry 1). However, it only gave rise to
partially recycled starting materials together with -amido
sulfone 49 as the only identifiable product. A number of
conditions were examined but all failed to form the long-chain
amido sulfone based on these two substrates (for details, see
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The Journal of Organic Chemistry
53 was suppressed by changing the reaction solvent to
revealed that the use of phosphine ligands had detrimental
effects on product formation,41 presumably due to the facile
displacement of the methoxy group in the acetal moiety (for
cyclohexane, allowing 52 to be isolated in a combined yield
up to 93% favoring a (2S,18S)-configured diastereomer
(Scheme 4).48 Interestingly, without an external nucleophile,
N,O-acetal 41 was fully recovered (> 90%) even after
refluxing in the same solvent overnight. The equilibrative
formation of N,O-acetal via a N-lactoyl imine was confirmed
by an isotopic-labeling experiment preformed with d3-
1
2
3
4
5
6
details,
see
SI
of
ref.
17).
Finally,
tris(dibenzylideneacetone)dipalladium (20 mol%) in DMF at
23 °C was selected as the optimal condition for the scale-up
preparation of 38 with an improved yield of 57%.42
7
methanol. This imine intermediate, albeit at
a
low
8
9
Scheme 4. Thermoregulated Mannich Reaction of the
Intramolecular Model Studies.
concentration, can be irreversibly trapped by lactone 32.48 This
initial success to assemble an intermolecular model system of
the lactonic core via N,O-acetal-based Mannich chemistry
convinced us that the biomimetic macrocyclization strategy
would be rewarding if an improved stereofacial control to the
imine could be realized. Additionally, decarboxylation of the
Mannich adduct under macrocyclic stereocontrol was
anticipated to be more stereoselective in installing the C2
stereogenic center present in lankacyclinol.49,50
TBSO
Me
O
TBSO
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TBSO
Me
O
32
lactone
+
Bu3Sn HN
Me HN
O
protonic
or Lewis acids
Bu3Sn
N
H
Me
OMe
Bu3Sn
OMe
51
50
41
or other protodestannylation products
32
lactone
solvent, reflux
TBSO
Me
O
HN
18
O
52
, dr (C2/C18)
SS : SR : RR
solvent
toluene
53
Me
HN
2
+
Me
O
44% (3.8:1.4:1)
c-hexane 93% (2.8:1.5:1)
55%
6%
O
Bu3Sn
Explorations on Mannich Macrocyclization. The pivotal
biomimetic Mannich macrocyclization was thus conducted in
refluxing cyclohexane at a concentration of 0.5 mM (Table 2,
entry 1). Three macrocyclized Mannich adducts 36a-c were
isolated in a combined yield of 46% in a ratio of 6.4:1.0:1.8
(36a:36b:36c). Extensive NMR analysis revealed that these
macrocycles were exclusively derived from the -addition
(C2) of the enolate carbon to the imine (C18). As suggested by
the presence of a diagnostic NOE interaction between C5-H
and C2-Me (for comprehensive presentations of their
individual COSY, NOESY and HMBC correlations, see SI,
Figure S3), only the major diastereomer 36a has the desired
stereochemistry at C2. Additionally, the absolute
configurations of newly established stereocenters at C18 in
36a and 36b were both inferred to be the (R)-configuration
based on their successful advancements to lankacyclinol (vide
infra). The participation of the presumptive N-lactoyl
azahexatriene species 56 in the Mannich macrocyclization was
further ascertained by the coproduction of trienic enamide 57
and dihydropyridine 58. The former compound, isolated in an
11% yield as an extremely unstable single geometric isomer
bearing C17–C18 (Z)-alkene, appeared to arise by a 1,5-
sigmatropic hydrogen shift involving the C16-Me of the imine
s-cis conformer (s represents the C17–C18 single bond).
Moreover, 57 was found to be stable in refluxing cyclohexane
for 24 hours, thus supporting an irreversible nature of the N-
lactoyl imine-enamide tautomerism under experimental
conditions. Additionally, byproduct 58 with unassigned
stereochemistry at C14 might be derived from the initial trans-
to-cis isomerization of the trisubstituted ∆C16–C17 in the
intermediary azatriene system followed by a diastereoselective
6π-azaelectrocyclization51 (~9:1 ds). However, macrocycles
(i.e., 60) generated by intramolecular nucleophilic capture of
this ∆C16–C17 isomeric imine were not detected in the
reaction mixture. The reactive species 56 can otherwise
undergo hydrolysis by reacting with a trace amount of water
presented in the reaction system to afford all-trans polyenal
59, the same compound that may already exist as an
inseparable contaminant in the starting material 38 (5~15
wt.%).
53
52
slow
[1,5]-H
shift
irreversible
trapping by
CD3OH (1 equiv)
c-hexane, 80 °C
sealed tube
32
lactone
slow
-MeOH
NHR
Me
H
Me NR
41
OCD3
Isotopic-
labeling
experiment
NR
H
+MeOH
fast
54
(50% D)
55
s-cis-
55
s-trans-
ORTEP of the desilylated iodination
product of 2R,18R-52 (CCDC 1523790)
ORTEP of the desilylated iodination
52
product of 2S,18S- (CCDC 1523785)
The long-chain N,O-acetal 38 was the only viable
macrocyclization precursor for advancement to the
lankacidins. The next focus is to probe suitable N,O-acetal-
based conditions using an intermolecular variant (Scheme 4).43
However, the activated N-lactoyl iminium species in situ
generated from 41 under protonic or Lewis acidic conditions
severely suffered from either double bond isomerization
followed by recapture by methanol to produce 50 or
tautomerization to form trans-enamide 51, and they were
found to be reluctant to undergo Mannich addition with the
lactonic nucleophile (for details, see SI of ref. 17).44 To devise
a workaround, we became keenly aware of the alcohol
exchange phenomenon of N,O-acetals under pyrolytic
conditions reported by Ben-Ishai in 1960s.45 This thermal
demethoxylation of N,O-acetal has been recently resumed to
prepare some bench-stable C-phenyl-N-acyl imines.46
However, as a mild method for imine generation, its
application in a telescoped C–C bond-forming process has
received little attention from the synthetic community.47 Imine
55 could be formed as a transient species via a thermal
depletion of methanol, the conditions of which would not only
be strictly neutral and substrate-tolerant, but also facilitate the
nucleophilic addition. At the outset, heating a solution of 41
and 32 in toluene resulted in the Mannich adducts 52 in a 44%
yield, alongside a substantial amount of cis-configured
enamide 53. A survey of solvents revealed that formation of
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The crucial thermolytic stereogenic center-generating
Page 6 of 19
1
2
3
4
5
6
7
8
macrocyclization warrants some additional discussion. High-
dilution conditions were found to be necessary to ensure a
practical cyclization efficiency. When performed at a higher
substrate concentration (5 mM), the reaction was sluggish and
only 24% conversion of 38 was observed (Table 2, entry 2).
Attempts to enhance the diastereoselectivity for 36a by
introducing metal complexation has yet to be effective (entries
3–6). Utilization of nonpolar solvents with lower boiling
points such as cyclopentane and n-hexane resulted in either no
reaction or low conversion accompanied by unidentified side
products (entries 7 and 8). Intriguingly, a preference for the
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Optimization of the Thermoregulated Mannich Macrocyclization
Me
O
Me
O
TBSO
HN
Me
TBSO
HN
Me
O
TBSO
HN
Me
O
2
2
O
Me
Me
O
Me
Me
Me
O
O
Me
O
O
O
O
18R
18R
18S
Me
Me
Me
Me
Me
2S
2R
2R
Me
Me
Me
TBSO
TBSO
O
O
O
O
O
O
Mannich
macro-
cyclization
TBSO
OTBDPS TBSO
OTBDPS TBSO
OTBDPS
Me
36a
Me
36b
Me
36c
TBDPSO
TBDPSO
0.5 mM in
solvent
reflux
Me
O
O
O
O
O
TBSO
Me
Me
Me
Me Me
O
16
17
Me
OMe
O
NH
O
Me
Me
O
18
O
O
OTBDPS
18
14
HN
N
Me
TBSO
OTBDPS
TBSO
O
O
Me
O
N
Me
59
TBSO
TBSO
TBSO
OTBDPS
Me
Me
Me
OTBS
Me
57
N-acyl azahexatriene
N,O-acetal
38
TBSO
HN
56
58
Me
atmospheric
yielde (%) of
36a 36b 36c
36
conversione
38
yielde (%) yielde (%)
entrya
solvent
Time
O
O
additive
O
boiling pointd
58
(dr
:
:
)
of
57
of
of
Me
cyclohexaneb
cyclohexanec
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclopentane
n-hexane
Me
1
2
3
4
5
6
7
8
9
80.7 °C
80.7 °C
80.7 °C
80.7 °C
80.7 °C
80.7 °C
49.3 °C
69.0 °C
76.8 °C
83.5 °C
80.1 °C
81.0 °C
110.6 °C
103.5 °C
138.5 °C
131.8 °C
22 h
22 h
20 h
25 h
22 h
22 h
48 h
60 h
22 h
22 h
24 h
22 h
6 h
100%
24%
100%
100%
53%
46 (6.4 : 1.0 : 1.8)
14 (7.8 : 1.0 : 4.2)
31 (3.6 : 1.0 : 2.2)
29 (2.9 : 1.0 : 2.3)
21 (4.4 : 1.0 : 3.0)
13 (5.8 : 1.0 : 3.3)
11
4
NDf
6
–
6
–
–
–
7
7
–
3
3
8
9
18
Me
O
NDf
7
Yb(fod)3 (5 mol%)
OTBDPS
TBSO
Pr(fod)3 (5 mol%)
Er(fod)3 (5 mol%)
Cu(fod)2 (5 mol%)
9
Me
10
7
60
(not obtained)
47%
< 5%
63%
g
–
–
–
8
7
12
4
10 (2.7 :
17 (1.1 :
20 (1.0 :
0
0
0
: 1.0)
: 1.0)
: 1.2)
TBSO
HN
tetrachloromethane
100%
100%
100%
100%
100%
100%
100%
100%
Me
10 1,2-dichloroethane
benzene
12 hexafluorobenzene
13 toluene
,,-trifluorotoluene
p-xylene
16 ethylcyclohexane
11
22 (2.1 : 1.0 : 2.9)
22 (4.2 : 1.0 : 3.8)
55 (6.9 : 1.0 : 6.1)
30 (2.3 : 1.0 : 2.4)
45 (5.4 : 1.0 : 4.7)
36 (3.2 : 1.0 : 2.2)
O
O
O
Me
Me
Me
O
15
12
25
10
14
15
22 h
2.5 h
2 h
TBSO
OTBDPS
Me
(not obtained)
a
38
All reactions were carried out on a 0.03 mmol scale and a concentration of
scale. c Carried out on a concentration of 5 mM. d From CRC Handbook of Chemistry and Physics, 91st ed. Haynes, W. M., Ed.; CRC Press: Boca
38 36
was 0.5 mM unless otherwise noted. b Carried out on a 0.3 mmol
61
Raton, FL, 2010. e Conversions of
and diastereoselectivities of
were calculated after isolation. f Not determined. g Not obtained.
formation of cyclization products with R-configured
quaternary stereocenters was observed when chlorinated
aliphatic solvents such as tetrachloromethane and 1,2-
dichloroethane (entries 9 and 10), or aromatic solvents were
applied (entries 11–15). In particular, upon changing the
solvent from cyclohexane to toluene, the cyclization occurred
with an increased efficiency, allowing the macrocycles to be
isolated in 55% yield in a ratio of 6.9:1.0:6.1 (36a:36b:36c)
within 6 hours. At refluxing temperatures higher than 130 °C,
the serviceable yields of Mannich adducts (36% for
ethylcyclohexane, 45% for p-xylene) were achieved, but
increased amounts of 57 or 58 were generated. Given the
molecular complexity rapidly generated as well as the
operational simplicity observed in this biomimetic
macrocyclization, the isolated yield of 32% for the desired
(2S,18R)-diastereomer 36a is remarkable.
Unified Synthesis of Macrocyclic Lankacidins. By
procuring enough quantities of 36a, we were poised to finalize
the synthesis of our preliminary target lankacidinol (3). Global
deprotection of 36a was not trivial, as it needed to be executed
to tolerate the fragile β-oxo-δ-lactone as well as the dienylic
alcohol functionalities. A similar process using bis-TBS-
protected lankacidin C as a substrate was declared by the
Kende group to be unfruitful with all variants of fluoride-
based protocols.19b Indeed, exposure of 36a with either TBAF
or tris(dimethylamino)sulfonium difluorotrimethylsilicate
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The Journal of Organic Chemistry
(TASF) both resulted in considerable amounts of side products
from elimination of the C7-hydroxyl group. By using excess
1
2
3
4
5
6
7
8
9
water as a protic additive in TASF-mediated deprotection,52
decarboxylation occurred prior to the complete silyl removal,
affording lankacyclinol and its C2-epimer in a combined yield
of 75% (Scheme 5). The synthetic 5 proved to be identical in
all respects to natural (–)-lankacyclinol.4d,21c The high
selectivity for the 2S-isomer (5/62, 12:1) may be attributed to
the Re-face selective protonation of the intermediary C3-
enolate with the stereocontrol imparted from the rigid
conformation of the polyene macrocyclic ring.49 Analysis of
the major product by X-ray diffraction unambiguously
confirms the configuration at C18 and provided the first solid
state topological structure of the decarboxylated lankacidin
macrocycles. After extensive experimentation (for details, see
SI of ref. 17), we uncovered a condition to liberate all of the
hydroxyl groups without disturbing the δ-lactone. In this
event, prolonged treatment of 36a with 40 wt.% HF in
acetonitrile at –20 °C gave (–)-lankacidinol (3) in a 51% yield
exhibiting spectroscopic properties in excellent agreement
with the literature reports from both Kinashi53 and Wang5.
Intriguingly, an isomeric substance 63 (Scheme 5, coined as
neolankacidinol) was also generated from the same reaction
mixture as a single diastereomer (43%), and the detailed NMR
studies unveiled a formal C7-hydroxyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Diversification of macrocycle 36a into six natural products of the lankacidin family, In the ORTEP
representations of acetate 66, the thermal ellipsoids are drawn at 20% probability.
HO
Me
HO
Me
O
Me
HO
Me
HO
Me
O
HN
O
Me
O
O
HN
O
Me
O
O
HN
O
Me
O
HN
O
O
HN
O
Me
Me
Me
Me
Me
Me
Me
+
Me
Me
Me
Me
Me
O
O
AcO
OH
AcO
OH
AcO
OH
HO
OH
HO
OH
Me
lankacyclinol A (
Me
lankacidinol A (4)
Me
lankacidin A (
Me
lankacyclinol (
[X-ray confirmed]
Me
2-epi-lankacyclinol (
[X-ray confirmed]
2
)
6
)
62
5
)
)
HOAc/TBAF, 2:1
THF, rt, 82%
TASF, H2O/DMF
rt, 79%
HOAc/TBAF, 2:1
THF, rt, 87%
TASF, H2O/DMF
rt, 75%
syn/anti = 12:1
R2O
HN
Me
Me
O
O
Me
O
1. 4 mol/L HCl
THF, 20 °C
3 h, 94% of
1. 4 mol/L HCl
TBSO
HN
Me
Me
O
THF, 20 °C
65
67
15 h, 87% of
(R1 = Ac, R2 = H)
O
O
O
O
HN
O
O
X-ray
(R1 = H, R2 = TBS)
Me
Me
Me
Me
Me
Me
Me
2. DMP, NaHCO3
CH2Cl2, rt
10 min, 80%
2. Ac2O, DMAP
Et3N, CH2Cl2
rt, 93%
O
O
O
R1O
OTBDPS
AcO
OTBDPS
TBSO
OTBDPS
Me
Me
68
Me
36a
: R1 = Ac, R2 = TBS
66
aq. HF, –20 °C
CH3CN, 38%
aq. HF, –20 °C
CH3CN, 43%
aq. 40 wt.% HF
CH3CN, –20 °C
aq. 40 wt.% HF
CH3CN, –20 °C
O
O
Me
H
H
H
Me
N
Me
OH
1 69
/ = 1:1
93%,
3 63
94%,
/
= 1:1
HO
HN
Me
O
H
H
H
H
O
HO
Me
O
O
Me
Me
Me
H
O
H
H
H
O
O
O
O
OH2
Me
Me
Me
H
HN
HN
Me
Me
Si
O
O
O
O
O
HN
O
Me
O
via
Me
Me
O
O
Me
Me
Me
Me
H
+
H
O
+
O
H
Me
Me
N
Me
OH
O
O
O
Me
Me
H
H
H
H
OH
HO
OH
OH
H
Re
HO
OH
O
H
H
H2O
H
H
Me
lankacidinol (
Me
Me
lankacidin C (
HO
neolankacidin C (
HO
neolankacidinol (
69
3
63
allylic carbocation
64
)
1
)
)
)
Scheme 6. Stereochemical Revision of Isolankacidinol, Isolankacyclinol and a Recently Isolated Lankacyclinol, In the
ORTEP representations of 10, 5, 62, and 74, the thermal ellipsoids are drawn at 20% probability.
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Page 8 of 19
HO
HN
Me
O
HO
HN
Me
O
TBSO
HN
Me
O
HO
HN
Me
O
1
2
3
4
5
6
7
8
B
A
aq. 40 wt.% HF
CH3CN, –20 °C
O
O
O
O
O
retro oxa-
Machael
O
O
X-ray
18R
Me
Me
Me
2
Me
Me
Me
Me
Me
2R
Me
Me
Me
Me
OH
82%, No 1,5-OH
migration product
pyridine,
heat
O
O
O
O
7
: ~5%
HO
OH
HO
OH
TBSO
OTBDPS
HO
OH
Me
Me
lankacidinol (3)
Me
36b
Me
-keto acid
70
isolankacidinol (10)
revised structure
Harada's
condition
5
62
: 67%
: 12%
oxa-
Machael
Harada's biosynthetic proposal
and base degradation studies
for isolankacidinol (1975, ref.4d)
C
9
HO
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
HN
O
Me
aq. 2 wt.%
K2CO3
+
Me
isolankacyclinol
71
enonic C3-C4 s-
trans/cis isomeric
Me
(
), reported as
5
MeOH, 25 °C, 1 h
O
5 71
:
, 4.4:1
HO
OH
5
to lankacyclinol (
)
Me
isolankacidinol (
reported structure
62
2-epi-lankacyclinol (
)
X-ray of
tris-(4-bromobenzyl ester)
5
7
)
lankacyclinol (
)
74
revised structure of
p-BrBzCl
Et3N, quant.
isolankacyclinol
HO
HN
Me
O
HO
HN
Me
TBSO
HN
Me
HO
HN
Me
Me
HO
HN
Me
aq. 40 wt.% HF
CH3CN, –20 °C
TASF, H2O
O
DMF, rt
Me
O
O
O
O
O
O
Me
O
O
O
Me
18
S
75 76
85%, / = 1.8:1
Me
Me
Me
Me
Me
Me
Me
+
+
2
R
Me
O
Me
86%
or HOAc/TBAF, 2:1
75
Me
Me
O
O
O
syn/anti = 9:1
O
THF, rt, : 76%
OTBDPS
7
HO
OH HO
OH
TBSO
HO
OH HO
OH
Me
2,18-bis-epi-lankacyclinol (
Me
18-epi-lankacyclinol (
Me
36c
Me Me
75
2,18-bis-epi-lankacidinol ( )
2,7,18-tri-epi-lankacidinol (
72
73
)
)
76
)
shift took place along the diene chain in
a
highly
pyruvoyl substitution at the nitrogen, the C24-hydroxy group
was selectively liberated from 66 by prolonged exposure to
aqueous HCl, and subsequently oxidized by Dess–Martin
periodinane to afford pyruvamide 68 (70% over two steps).
Removal of the TBDPS group by utilizing HOAc/TBAF in
THF completed the synthesis of (–)-lankacidin A (2), while (–
)-lankacidin C (1)19 was obtained along with its hydroxyl-
migrated congener 69 (referred to as neolankacidin C) by
desilylation conducted with aqueous hydrofluoric acid in
acetonitrile at –20 °C. The spectral data of the synthetic
natural products (1,2 and 4) were in good agreement with
literature values.53
stereoselective manner (for comprehensive presentations of its
COSY, NOESY and HMBC correlations, see SI of ref. 17). It
was quickly discovered that 63 could equilibrate with 3 under
identical desilylation conditions, thus maximizing the material
throughput to access the natural product. This process is
assumed to involve a cationic intermediate 64, which
undergoes a nonregioselective reversible hydration reaction
under a macrocyclic stereocontrol.49,54 While numerous reports
concerning the degradation chemistry of lankacidin antibiotics
exists,4c,d,7c to the best of our knowledge, the acid-promoted
hydroxyl transportation reaction within the lankacidin skeleton
has never been reported in the literature.
Structural
Revision
of
Isolankacidinol
and
Having conquered lankacidinol and lankacyclinol, we
continued to synthesize other macrocyclic members of the
same family (Scheme 5). To this end, removal of the TBS
group at the C7 position of 36a was smoothly realized by
aqueous HCl in THF (with the final concentration of HCl in
the reaction system to be ~0.3 M) at 20 °C for 3 hours. It is
important to note that prolonged reaction time (> 20 h) would
lead to a complex mixture of products. Acetylation of the
resultant allylic alcohol 65 delivered acetate 66, the structure
and absolute stereochemistry of which were unambiguously
determined by single-crystal X-ray diffraction. Upon
employing the same condition established for 5,
transformation of 66 into (–)-lankacyclinol A (6) proceeded
with an equal efficiency (79%). An intended global
desilylation of 66 by treatment with aqueous HF in acetonitrile
at –20 °C resulted in the complete hydrolysis of the C7-
acetate. Another round of experiments identified a 2:1 molar
mixture of HOAc/TBAF to be an optimal combination for this
desilylation, being capable of delivering (–)-lankacidinol A (4)
in an 82% yield. To access the last two targets bearing a
Isolankacyclinol. The NOE correlations of C2-Me with C4-H
and lack of the cross peak between C2-Me with C5-H
observed in 36b and 36c indicated they possessed the same -
Me configuration at the quaternary carbon C2. However, the
least predominant isomer 36b (only 5% isolated yield from
38) attracted our attention in the process of spectral
comparison with the previously identified 36a, which has -
Me configuration at C2. A large upfield-shift for C5-H proton
signal (from  4.29 to  3.52) and a downfield-shift for C4-H
proton signal (from  2.34 to  2.66) were observed, which are
reported by Harada and coworkers to be diagnostically
characteristic of isolankacidinol.4d For further clarification,
36b was desilylated by treatment with HF in aqueous
acetonitrile at –20 °C for 60 hours and no formal 1,5-hydroxy
migration product was observed (Scheme 6A). More
surprisingly, the NMR spectra and optical rotation (observed
25
25
[]D = –189 (c = 0.13, EtOH); lit: []D = –190 (c = 0.53,
EtOH)4d) for synthetic macrocycle 10 matched those reported
for isolankacidinol,53,55 which was unfortunately assigned as
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The Journal of Organic Chemistry
the C5-epimer of lankacidinol as shown in 7 (Scheme 6B).4d
decarboxylated variant 75 might be an as-yet-undiscovered
1
2
3
4
5
6
7
8
The structure and absolute configuration of 10 was further
unequivocally established by X-ray crystallographic analysis
(Cu K), allowing a stereochemical revision of the originally
proposed structure of isolankacidinol (7) to be C2-epimer of
lankacidinol (10). This result implies that the documented
conversion from lankacidinol to isolankacidinol might initially
involve a retro-Mannich reaction to open the 17-membered
macrocycle rather than the retro-oxa-Michael cleavage of the
lactonic C5–O bond. In fact, the enone carboxylate
intermediate 70, as suggested in the original biogenesis
proposal, by the present view might be especially prone to
decarboxylation to release lankacyclinol.56 Moreover, the
natural occurrence of 2-epi-lankacidinol as a minor congener,
as validated by our work, unraveled for the first time the
imperfect facial selective nature posed in the enzymatic
lankacidin macrocycle-forming process. In addition, the highly
stereoselective decarboxylation event realized from either
lankacidinol (3) or its C2-epimeric skeleton under abiotic
conditions also provided valuable insights into the biogenesis
of 5.
natural product. Toward this end, 36c was desilylated under
previously established acidic conditions (aq. HF/CH3CN at –
20 °C) to give 75 in 55% yield, along with its C7-epimer 76 in
30% yield (for detailed 2D-NMR analysis of 75 and 76, see
SI, Figure S4). This unexpected scenario as compared with
those of 36a/b further indicates the sophistication of the
chemo- and stereoselectivity profiles stemming from the
C2/C18-configuration-dependent conformational change.
Upon changing the reagent system to HOAc/TBAF (2:1),
global desilylation of 36c occurred with no C7-epimerization
to provide the “missing” natural product 2,18-bis-epi-
lankacidinol (75) in 76% yield.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSION
In summary, we have detailed the evolution of a unified
biomimetic approach to the capacity of all known macrocyclic
lankacidins in the longest linear 7–12 steps from readily
available starting materials (such as 44 and 45). By taking
advantage of the thermolysis chemistry of N,O-acetal to
generate the requisite N-acyl-1-azahexatriene species, we
In the same publication,4d
a non-naturally-occurring
realized
the
projected
stereoselective
Mannich
substance, isolankacyclinol (71) was obtained as a minor base
degradation product of isolankacidinol (Scheme 6B), and its
structure was postulated to be s-trans/cis (s represents enonic
single bond C3–C4 in the enone portion) isomeric to
lankacyclinol (5). To probe this unusual isomerism
phenomenon, the synthetic sample of isolankacidinol (10) was
subjected to the literature-described conditions (aqueous 2
wt.% K2CO3 in methanol, 25 °C), two decarboxylated
compounds were isolated in excellent combined yield
(67%+12%). The major product was readily identified as 5,
which is in accordance with the Harada’s result. The minor
product was assigned as 2-epi-lankacyclinol (62). X-ray
crystallographic analysis unambiguously confirmed this
assignment, and further validated both macrocycles (5 and 62)
existed as enonic s-trans conformers in solid states. Though no
NMR spectra were provided by Harada for direct comparison,
it is highly probable that isolankacyclinol and 2-epi-
lankacyclinol might be identical.
macrocyclization, from the products of which all the
macrocyclic lankacidins, including the relatively low-abundant
and stereochemically unique isolankacidinol can be conquered
by orchestrated desilylative manipulations.
Our work not only constitutes, to our knowledge, the first
example of macrocyclic construction (> 14-membered) via a
Mannich reaction in the context of complex natural product
synthesis but also corroborates, for the first time, the chemical
feasibility of the Arakawa-Kinashi’s biogenetic hypothesis for
the formation of the lankacidin macrocycle. Moreover, the
bioinspired strategy-enabled reassignments of the reported
structure of isolankacidinol (7 to 10), combined with the
discovery of a recently isolated lankacyclinol to be in fact its
2,18-bisepimer (72), unraveled a previously underappreciated
nature of product diversity58 arising from the late-stage
enzymatic oxidative cyclization in lankacidin biosynthesis. In
addition, our decarboxylation experiments conducted under
mild abiotic conditions with moderate to high selectivities not
only shed light upon the dominant occurrence of 2,18-syn
isomers (5, 6 and 72) in the natural resources, but at the same
time strongly implicate that both their precursors (i.e. 75 and
as-yet-unisolated 36d) and minor C1-depleted congeners (i.e.
isolankacyclinol 62 and 73) are potentially undiscovered
natural products. Apart from these benefits, the most notable
one provided by a biomimetic strategy is the significantly
reduced step count compared with two previous entries to
macrocyclic lankacidins.19,20c Collaborative efforts to explore
new analogues for biological mode-of-action investigations as
well as to delineate the macrocyclization stereocontrol exerted
by the active site of the enzyme are continuing and will be
reported in due course.
2,18-Bis-epi-Lankacyclinol:
A New Natural Product.
During the investigation of the base degradation chemistry of
10, we keenly noticed that the 1H and 13C NMR spectra of our
synthetic lankacyclinol (5) collected in CD3OD differed
significantly from those of a recently isolated lankacyclinol
sample.57 This led us to speculate the real structure of the latter
might be a diastereoisomer of 5 with the opposite C2/C18-
stereochemistry. Thus, the remaining (2R,18S)-diastereomer
36c was exposed to TASF in wet DMF, smoothly furnishing
two decarboxylated products in excellent yield with a ratio of
9:1 for 72/73 (Scheme 6C). To our delight, the predominant
3
2,18-syn-isomer bearing a large JH,H coupling constant
between H-2 and H-18 (10.3 Hz) was found to exhibit spectral
properties identical with those reported by Wang.57 This
reassignment was further ascertained by single-crystal X-ray
diffraction conducted with its tris-(4-bromobenzyl ester)
derivative 74. The syn-selective decarboxylation observed for
36a-c underscores the powerful stereodirecting influence of
the rigid macrocyclic conformation.49 The elucidation of the
existence of 72 in natural environment suggests its non-
EXPERIMENTAL SECTION
All non-aqueous reactions were conducted in oven-dried glassware
fitted with rubber septa and magnetically stirred under N2 atmosphere
unless otherwise noted. Anhydrous solvents were obtained using
standard drying techniques. All commercial grade reagents were used
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The Journal of Organic Chemistry
Page 10 of 19
without further purification unless stated otherwise. Flash
7.2 Hz, 3H), 1.35/1.34* (d, J = 6.8 Hz, 3H), 0.93 (s, 9H), 0.12/0.11* (s,
chromatography was performed on 230-400 mesh silica gel (Silicycle
flash F60) with the indicated solvent systems. Yields refer to
chromatographically and spectroscopically homogeneous material.
Reactions were monitored by thin layer chromatography (TLC)
supplied by Yantai Jiangyou Silicon Material Company (China).
NMR spectra were recorded on Varian mercury–400, Bruker AM–
400, and Bruker AV–500 spectrometers and chemical shifts are
reported in ppm down field from TMS, using residual 1H and 13C
signals of the solvent (CDCl3:  7.26, 77.16 ppm; CD3OD:  3.31,
49.00 ppm; DMSO-d6:  2.50, 39.52 ppm; acetone-d6:  2.05, 29.84,
206.26) as an internal standard. Data are reported as: (s = singlet, br =
broad, d = doublet, t = triplet, q = quartet, m = multiplet; J = coupling
constant in Hz, integration.). Optical rotations were measured on a
Jasco P–1030 digital polarimeter using a 100 mm path-length cell at
589 nm. High-resolution mass spectra (HRMS) were acquired through
the National Center for Organic Mass Spectrometry in Shanghai on a
Thermo Fisher Scientific LTQ FT Ultra mass spectrometer (mass
analyzer type: Fourier transform ion cyclotron resonance (FT-ICR))
with DART (Direct Analysis in Real Time) ionization performed in
positive mode. Infrared spectra were recorded as thin films on NaCl
plates on a Perkin–Elmer 983 or Digital FT-IR spectrometer and are
reported in frequencies of absorption given in reciprocal centimeters
(cm-1).
3H), 0.10 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 171.9
(2 peaks), 136.9 (2 peaks), 133.9 (2 peaks), 129.3 (2 peaks), 129.0 (2
peaks), 127.8, 127.6, 105.5, 105.2, 69.8, 62.2 (2 peaks), 25.9, 21.8,
18.2, 18.1, 14.0, 13.8, -4.4 (2 peaks), -5.2, -5.3 ppm; IR (thin film):
vmax = 3405, 3347, 2954, 2930, 2858, 1698, 1664, 1502, 1447, 1306,
1261, 1145, 1123, 1086, 970, 833, 783, 729, 691, 592, 552 cm-1;
HRMS-DART (m/z): calcd. for C19H32O4NSSi [M + H]+: 398.1816,
found: 398.1815.
1
2
3
4
5
6
7
8
N,O-acetal 50. This compound was obtained as a faint yellow oil
(32 mg, 23% yield) from the achiral phosphoric acid 34-catalyzed
model Mannich reaction between lactone 32 (0.20 mmol) and N,O-
acetal 41 (0.24 mmol) and exists as a 1.2 : 1 diastereomeric mixture.
TLC (petroleum ether / ethyl acetate = 20:1 v/v, KMnO4): Rf = 0.36;
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[]2D6 = −11.8 (c = 1.09 in CHCl3); H NMR (400 MHz, CDCl3): δ =
1
6.96/6.87* (d, J = 10.4 Hz, 1H), 6.00 (m, 1H), 5.40 (m, 1H),
4.19/4.26* (q, J = 6.8 Hz, 1H), 3.30/3.29* (s, 3H), 1.94/1.96* (d, J =
3
1.2 Hz, JSn-H = 20.2 Hz, 3H), 1.52-1.44 (m, 6H), 1.41/1.36* (d, J =
6.8 Hz, 3H), 1.33-1.25 (m, 6H), 0.97-0.87 (m, 24H), 0.12 (s, 3.0H),
0.10* (s, 1.5H), 0.07* (s, 1.5H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ = 174.3, 174.2, 145.8, 145.6, 136.0 (2 peaks), 80.6, 80.3,
70.1, 69.9, 54.9 (2 peaks), 29.2 (2 peaks), 27.4, 27.3, 27.2, 25.8, 25.7,
22.2, 21.8, 18.1, 18.0, 13.7, 10.7, 10.6, -4.6, -4.7, -5.3, -5.4 ppm; IR
(thin film): vmax = 3416, 2955, 2929, 1695, 1493, 1255, 1118, 1066,
832, 780 cm-1; HRMS-DART (m/z): calcd. for C25H52O2NSi112Sn [M
− OCH3]+: 538.2810, found: 538.2807.
The general procedure and the synthetic procedures and
characterization data of compounds 31, 32, 35, 38, 39, 41, 42–47, 52,
53, 59, 62 and 63, as well as the natural product NMR spectra
comparisons (5 in acetone-d6 and 3 in methanol-d4) have been
recorded in our previous work,17 and are not reproduced here.
Enamide 51. This compound was obtained as a colorless oil (17
mg, 13% yield) from the achiral phosphoric acid 34-catalyzed model
Mannich reaction between lactone 32 (0.20 mmol) and N,O-acetal 41
(0.24 mmol) TLC (petroleum ether / ethyl acetate = 15:1 v/v,
Synthesis of -amido sulfone 40. To a stirred solution of N,O-
acetal 41 (978 mg, 1.7 mmol, 1.0 equiv) in anhydrous CH2Cl2 (3.4
mL) was added triphenylphosphonium tetrafluoroborate (595 mg, 1.7
mmol, 1.0 equiv, predried in vacuo for > 24 hours prior to use to
remove H2O). Stirring was continued for 1 hour at room temperature
after which TLC analysis indicated the complete consumption of the
starting material. The solvent was evaporated under reduced pressure
and the remaining volatiles were completely removed in vacuum to
furnish a white, waxy solid. This material was dissolved in anhydrous
chloroform (3.4 mL) and treated with anhydrous sodium
benzenesulfinate (360 mg, 2.2 mmol, 1.3 equiv). The resultant
suspension was sonicated in a bath for 5 min and vigorously stirred
for additional 10 min at ambient temperature. The reaction mixture
was then concentrated under reduced pressure and rapidly purified by
a silica gel column (petroleum ether/EtOAc: 10/1) to afford 40 (626
mg, 54% yield) as a pale-yellow oil and 1.5 : 1 diastereomeric
mixture. TLC (petroleum ether / ethyl acetate = 4:1 v/v, KMnO4): Rf
KMnO ): R = 0.69; []2D4 = −18.3 (c = 1.04 in CHCl3); 1H NMR (400
4
f
MHz, CDCl3): δ = 8.25 (d, J = 10.8 Hz, 1H), 6.86 (dd, J = 14.4 Hz,
11.2 Hz, 1H), 6.09 (d, J = 14.0 Hz, 3JSn-H = 35.6 Hz, 1H), 5.78 (d, J =
3
3
2.6 Hz, JSn-H = 61.6 Hz, 1H), 5.16 (d, J = 2.6 Hz, JSn-H = 28.8 Hz,
1H), 4.26 (q, J = 6.8 Hz, 1H), 1.56-1.48 (m, 6H), 1.40 (d, J = 6.4 Hz,
3H), 1.35-1.28 (m, 6H), 1.03-1.99 (m, 6H), 0.95 (s, 9H), 0.90-0.86 (m,
9H), 0.13 (s, 3H), 0.11 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ = 171.5, 148.9, 126.4, 124.4, 121.9, 69.9, 29.2, 27.4, 25.9,
21.8, 18.2, 13.8, 10.0, -4.4, -5.2 ppm; IR (thin film): vmax = 3413,
2956, 2929, 2857, 1701, 1643, 1492, 1260, 1118, 960, 897, 832, 781
cm-1; HRMS-DART (m/z): calcd. for C25H52O2NSi112Sn [M + H]+:
538.2810, found: 538.2813.
Deuterated N,O-acetal 54 from isotopic labeling experiment. A
3 mL-pressure vessel equipped with a magnetic stirring bar was
charged with a solution of N,O-acetal 41 (146 mg, 0.25 mmol, 1.0
equiv, as an inseparable 1.4 : 1 diastereomeric mixture) in degassed
cyclohexane (2.5 mL). CD3OH (8.8 mg, 10.1 L, 1.0 equiv, 99.8
atom % D) was added in one portion. The vial was sealed tightly,
immersed into a preheated oil bath at 80 C with stirring and kept at
this temperature for 17 hours. The reaction was cooled to room
temperature before all volatiles were removed in vacuo. The crude
= 0.50; []2D3 = −8.9 (c = 1.11 in CHCl3); 1H NMR (400 MHz, CDCl3):
δ = 7.93-7.88 (m, 2H), 7.64-7.61 (m, 1H), 7.54-7.49 (m, 2H),
7.31/7.24* (d, J = 10.2 Hz, 1H), 6.08/6.05* (dd, J = 10.2, 5.6 Hz, 1H),
5.49 (dq, J = 8.8, 1.6 Hz, 3JSn-H = 30.4 Hz, 1H), 4.10/4.08* (q, J = 6.6
Hz, 1H), 1.90/1.79* (d, J = 1.6 Hz, 3JSn-H = 20.9 Hz, 3H), 1.51-1.44 (m,
6H), 1.37-1.25 (m, 9H), 0.98-0.88 (m, 24H), 0.18 (s, 1.1H), 0.13 (s,
1.1H), 0.09* (s, 1.6H), 0.04* (s, 1.6H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ = 173.1, 173.0, 155.4, 154.9, 136.9 (2 peaks), 134.0, 133.9,
129.5, 129.4, 129.0, 128.9, 126.2, 125.7, 69.9, 69.6, 65.7, 65.3, 29.0,
27.4 (2 peaks), 25.8, 21.7, 21.4, 20.7, 20.5, 18.0 (2 peaks), 13.8 (2
peaks), 9.4, -4.5 (2 peaks), -5.2, -5.5 ppm; IR (thin film): vmax = 3409,
2955, 2929, 2856, 1699, 1493, 1321, 1150, 1118, 832, 781 cm-1;
HRMS-DART (m/z): calcd. for C31H58O4NSSi112Sn [M + H]+:
680.2899, found: 680.2896.
1
material was subjected to H NMR analysis and about 1 : 1 D : H
incorporation with respect to methoxyl groups was observed. [Note]:
this ratio of deuteration did not change when reaction time was
prolonged, thus indicating that an equilibrium state had been reached.
When the above mixture was resubjected to the same conditions over
several cycles, an analytically-pure sample of 54 (141 mg, 97%) with
more than 50 : 1 (D : H) incorporation can be obtained as a colorless
oil and as 1.4 : 1 diastereomeric mixture for characterization purposes.
TLC (petroleum ether / ethyl acetate = 15:1 v/v, KMnO4): Rf = 0.33;
[]2D4 = −12.3 (c = 1.29 in CHCl3); H NMR (400 MHz, CDCl3): δ =
It was discovered that 40 exerted a pronounced tendency to
undergo clean conversion to give 49 on contact with silica gel or
during prolonged storage at room temperature, and should be kept at
1
6.98/6.90* (d, J = 10.0 Hz, 1H), 5.82/5.80* (dd, J = 9.6, 6.4 Hz, 1H),
5.54 (dq, J = 6.8, 2.0 Hz, 3JSn-H = 32.4 Hz, 1H), 4.19/4.26* (q, J = 6.8
Hz, 1H), 1.90/1.90* (d, J = 2.0 Hz, 3JSn-H = 22.4 Hz, 3H), 1.50-1.43 (m,
6H), 1.41/1.35* (d, J = 6.8 Hz, 3H), 1.33-1.25 (m, 6H), 0.91-0.85 (m,
24H), 0.10 (s, 3.6H), 0.08* (s, 1.2H), 0.04* (s, 1.2H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ = 174.5, 174.4, 146.4 (2 peaks), 136.9,
−20 C in a refrigerator. []2D6 = −20.9 (c = 1.19 in CHCl3); 1H NMR
(400 MHz, CDCl3): δ = 8.29/8.27* (d, J = 10.4 Hz, 1H), 7.83-7.80 (m,
2H), 7.65-7.61 (m, 1H), 7.54-7.50 (m, 2H), 6.66/6.63* (dd, J = 14.4,
10.4 Hz, 1H), 5.18/5.16* (dd, J = 14.4, 8.4 Hz, 1H), 4.21/4.29* (q, J =
6.8 Hz, 1H), 3.71/3.70* (dq, J = 8.4, 7.2 Hz, 1H), 1.44/1.43* (d, J =
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136.7, 76.3, 75.8, 70.1, 69.9, 54.3 (m), 29.2 (2 peaks), 27.5, 27.4, 25.8,
1683, 1506, 1472, 1460, 1253, 1111, 1074, 963, 835, 779, 702, 507
cm-1; HRMS-DART (m/z): calcd. for C53H82O7NSi3 [M + H]+:
928.5394, found: 928.5395.
22.3, 21.9, 20.4, 18.1 (2 peaks), 13.8 (2 peaks), 9.3, 9.2, -4.6 (2 peaks),
-5.2, -5.3 ppm; IR (thin film): vmax = 3419, 2956, 2929, 2857, 1693,
1494, 1464, 1366, 1339, 1254, 1121, 1073, 1031, 978, 875, 834, 781,
669 cm-1; HRMS-DART (m/z): calcd. for C25H52O2NSi112Sn [M −
OCD3]+: 538.2810, found: 538.2812.
1
2
3
Macrocycle 36c. TLC (petroleum ether / ethyl acetate = 4:1 v/v,
KMnO ): R = 0.31; []2D3 = +49.8 (c = 1.13 in CHCl3); 1H NMR (500
4
f
4
5
6
7
8
9
MHz, CDCl3): δ = 8.06 (d, J = 10.0 Hz, 1H, H-N), 7.70-7.59 (m, 4H,
H-Ar), 7.42-7.30 (m, 6H, H-Ar), 6.22 (d, J = 15.5 Hz, 1H, HC9), 6.08
(d, J = 16.0 Hz, 1H, HC15), 5.47 (dd, J = 15.5, 3.5 Hz, 1H, HC14), 5.41
(dd, J = 15.5, 5.0 Hz, 1H, HC8), 5.39-5.35 (m, 2H, HC18, HC11), 4.99
(d, J = 10.0 Hz, 1H, HC17), 4.67 (m, 1H, HC13), 4.57 (m, 1H, HC7),
4.27 (q, J = 6.8 Hz, 1H, HC24), 3.84 (dt, J = 11.5, 5.5 Hz, 1H, HC5),
2.73 (dq, J = 11.5, 6.5 Hz, 1H, HC4), 2.25-2.19 (m, 1H, HAC12), 2.13-
2.08 (m, 1H, HBC12), 2.02-2.00 (m, 2H, HAC6, HBC6), 1.75 (s, 3H,
H3C22), 1.56 (s, 3H, H3C21), 1.49 (s, 3H, H3C19), 1.37 (d, J = 6.8 Hz,
3H, H3C25), 1.12 (d, J = 6.5 Hz, 3H, H3C20), 1.10 (s, 9H, SiR), 0.97 (s,
9H, SiR), 0.92 (s, 9H, SiR), 0.13 (s, 3H, SiR), 0.11 (s, 3H, SiR), 0.06 (s,
3H, SiR), 0.06 (s, 3H, SiR) ppm; 13C{1H} NMR (125 MHz, CDCl3): δ
= 209.6 (C3=O), 174.0 (C23=O), 172.2 (C1=O), 139.0 (C16), 136.0 (2
peaks, C9H, SiR), 134.9 (C10), 134.4 (SiR), 134.0 (SiR), 133.7 (C15H),
130.9 (C14H), 129.9 (SiR), 129.7 (SiR), 127.9 (C11H), 127.7 (SiR),
127.6 (SiR), 126.3 (C8H), 124.3 (C17H), 75.3 (C5H), 72.1 (C13H), 70.2
(C24H), 70.0 (C7H), 59.1 (C2), 52.0 (C18H), 45.5 (C4H), 42.2 (C6H2),
34.5 (C12H2), 27.3 (SiR), 26.1 (SiR), 25.9 (SiR), 23.3 (C19H3), 22.0
(C25H3), 19.5 (SiR), 18.4 (SiR), 18.2 (SiR), 13.2 (C22H3), 13.1 (C21H3),
9.2 (C20H3), -4.5 (SiR), -4.6 (SiR), -4.7 (SiR), -4.9 (SiR) ppm; IR (thin
film): vmax = 3415, 2956, 2930, 2890, 2857, 1750, 1713, 1679, 1498,
1252, 1111, 1077, 969, 833, 779, 702, 504 cm-1; HRMS-DART (m/z):
calcd. for C53H82O7NSi3 [M + H]+: 928.5394, found: 928.5389.
Biomimetic Mannich macrocyclization (Table 2, entry 1).
solution of 1:1 diastereomeric mixture of N,O-acetal 38 (320 mg, 0.31
mmol, contaminated by 6 wt.% polyenal 59 as indicated by NMR
A
analysis) in cyclohexane (20 mL) was added to
a refluxing
cyclohexane (600 mL) by cannula transfer. The reaction mixture was
stirred at reflux for 22 hours until complete disappearance of 3.31
ppm singlet methoxyl group signal as monitored by NMR analysis.
The solution was cooled to ambient temperature and concentrated to
give an oily residue, which was purified by preparative TLC (20%
EtOAc in petroleum ether) to afford macrocycle 36a (92 mg, 32%
yield), 36b (13 mg, 5% yield), macrocycle 36c (26 mg, 9% yield),
enamide 57 (32 mg, 11% yield), and dihydropyridine 58 (10 mg, 4%
yield), both as colorless oils.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Macrocycle 36a. TLC (petroleum ether / ethyl acetate = 4:1 v/v,
KMnO ): R = 0.40; []2D5 = −79.3 (c = 0.76 in CHCl3); 1H NMR (400
4
f
MHz, CDCl3): δ = 7.78 (d, J = 10.4 Hz, 1H, H-N), 7.68-7.61 (m, 4H,
H-Ar), 7.42-7.29 (m, 6H, H-Ar), 5.86 (d, J = 15.6 Hz, 1H, HC9), 5.64
(dd, J = 15.6, 9.4 Hz, 1H, HC8), 5.53 (dd, J = 16.0, 8.4 Hz, 1H, HC14),
5.47 (t, J = 10.8 Hz, 1H, HC18), 5.24 (d, J = 16.0 Hz, 1H, HC15), 4.99
(dd, J = 11.2, 5.2 Hz, 1H, HC11), 4.50 (d, J = 10.8 Hz, 1H, HC17), 4.29
(dt, J = 12.0, 2.8 Hz, 1H, HC5), 4.24 (m, 1H, HC7), 4.20 (q, J = 6.8 Hz,
1H, HC24), 3.98 (ddd, J = 10.8, 8.4, 4.0 Hz, 1H, HC13), 2.47 (m, 1H,
HAC12), 2.34 (dq, J = 12.0, 6.8 Hz, 1H, HC4), 2.28-2.21 (m, 2H, HBC12,
HAC6), 2.08 (m, 1H, HBC6), 1.83 (s, 3H, H3C22), 1.51 (s, 3H, H3C21),
1.39 (d, J = 6.8 Hz, 3H, H3C25), 1.35 (s, 3H, H3C19), 1.17 (d, J = 6.8
Hz, 3H, H3C20), 1.04 (s, 9H, SiR), 0.95 (s, 9H, SiR), 0.83 (s, 9H, SiR),
0.11 (s, 3H, SiR), 0.09 (s, 3H, SiR), 0.01 (s, 3H, SiR), -0.03 (s, 3H, SiR)
ppm; 13C{1H} NMR (125 MHz, CDCl3): δ = 211.1 (C3=O), 174.1
(C23=O), 170.3 (C1=O), 138.9 (C16), 137.1 (C9H), 136.4 (C10), 136.0
(Ar), 135.9 (Ar), 134.5 (Ar), 134.2 (Ar), 133.7 (C15H), 131.5 (C14H),
130.0 (C8H), 129.7 (2 peaks, Ar), 128.0 (C11H), 127.7 (Ar), 127.6
(Ar), 124.7 (C17H), 76.3 (C13H), 75.7 (C5H), 71.0 (C7H), 70.3 (C24H),
57.1 (C2), 51.0 (C18H), 46.4 (C4H), 38.5 (C6H2), 37.9 (C12H2), 27.1 (2
peaks, SiR), 25.9 (2 peaks, SiR), 22.3 (C25H3), 20.9 (C19H3), 19.3 (SiR),
18.2 (SiR), 12.9 (C22H3), 12.8 (C21H3), 9.7 (C20H3), -3.7 (SiR), -4.4
(SiR), -4.6 (SiR), -5.1 (SiR) ppm; IR (thin film): vmax = 3415, 2928,
2856, 1753, 1710, 1680, 1501, 1471, 1259, 1062, 963, 834, 802, 702
cm-1; HRMS-DART (m/z): calcd. for C53H82O7NSi3 [M + H]+:
928.5394, found: 928.5374.
Long-chain enamide 57. TLC (petroleum ether / ethyl acetate =
4:1 v/v, KMnO ): R = 0.33; []2D3 = −7.5 (c = 1.02 in CHCl3); H
1
4
f
NMR (400 MHz, CDCl3): δ = 8.72 (d, J = 11.6 Hz, 1H, H-N), 7.67-
7.60 (m, 4H, H-Ar), 7.42-7.26 (m, 6H, H-Ar), 6.87 (dd, J = 11.6, 9.4
Hz, 1H, HC18), 6.16 (d, J = 16.0 Hz, 1H, HC9), 5.97 (d, J = 15.6 Hz,
1H, HC15), 5.70 (dd, J = 15.6, 6.4 Hz, 1H, HC14), 5.46 (dd, J = 15.6,
7.6 Hz, 1H, HC8), 5.42 (t, J = 7.6 Hz, 1H, HC11), 5.18 (d, J = 9.4 Hz,
1H, HC17), 5.14 (s, 1H, HBC22), 5.06 (s, 1H, HAC22), 4.53 (m, 1H,
HC7), 4.35-4.23 (m, 3H, HC5, HC13, HC24), 3.46 (q, J = 6.8 Hz, 1H,
HC2), 2.43-2.35 (m, 2H, HC4, HAC12), 2.30-2.23 (m, 1H, HBC12), 2.06-
1.99 (m, 1H, HAC6), 1.96-1.89 (m, 1H, HBC6), 1.59 (s, 3H, H3C21),
1.39 (d, J = 6.8 Hz, 3H, H3C25), 1.32 (d, J = 6.4 Hz, 3H, H3C19), 1.18
(d, J = 7.6 Hz, 3H, H3C20), 1.04 (s, 9H, SiR), 0.89 (s, 9H, SiR), 0.88 (s,
9H, SiR), 0.10 (s, 3H, SiR), 0.06 (s, 6H, SiR), 0.03 (s, 3H, SiR) ppm;
13C{1H} NMR (125 MHz, CDCl3): δ = 204.5 (C3=O), 172.0 (C23=O),
169.7 (C1=O), 140.7 (C16), 136.3 (C9H), 136.1 (SiR), 134.8 (C14H),
134.7 (C10), 134.3 (SiR), 134.2 (SiR), 131.0 (C15H), 129.8 (SiR), 129.7
(SiR), 128.9 (C11H), 128.7 (C8H), 127.7 (SiR), 127.6 (SiR), 122.6
(C18H), 117.2 (C22HAHB), 108.3 (C17H), 76.8 (C5H), 73.7 (C13H), 70.6
(C7H), 70.0 (C24H), 50.3 (C2H), 46.8 (C4H), 41.3 (C6H2), 37.3 (C12H2),
27.2 (SiR), 26.0 (SiR), 25.9 (SiR), 21.9 (C25H3), 19.5 (SiR), 18.3 (SiR),
18.1 (SiR), 12.8 (C21H3), 12.5 (C20H3), 8.1 (C19H3), -4.0 (SiR), -4.6 (2
peaks, SiR), -5.0 (SiR) ppm; IR (thin film): vmax = 3402, 2955, 2929,
2857, 1765, 1725, 1699, 1654, 1489, 1390, 1362, 1255, 1112, 1074,
836, 779, 702 cm-1; HRMS-DART (m/z): calcd. for C53H82O7NSi3 [M
+ H]+: 928.5394, found: 928.5397.
Macrocycle 36b. TLC (petroleum ether / ethyl acetate = 4:1 v/v,
KMnO ): R = 0.52; []2D4 = −83.3 (c = 0.80 in CHCl3); 1H NMR (500
4
f
MHz, CDCl3): δ = 7.67-7.59 (m, 4H, H-Ar), 7.49 (d, J = 10.0 Hz, 1H,
H-N), 7.40-7.29 (m, 6H, H-Ar), 6.02 (d, J = 15.5 Hz, 1H, HC9), 5.60
(t, J = 10.5 Hz, 1H, HC18), 5.46 (dd, J = 16.0, 7.5 Hz, 1H, HC14), 5.38
(d, J = 16.0 Hz, 1H, HC15), 5.18 (dd, J = 15.5, 8.0 Hz, 1H, HC8), 4.99
(m, 1H, HC11), 4.76 (d, J = 10.0 Hz, 1H, HC17), 4.40 (m, 1H, HC7),
4.22 (q, J = 6.5 Hz, 1H, HC24), 4.11 (m, 1H, HC13), 3.52 (t, J = 10.5
Hz, 1H, HC5), 2.66 (dq, J = 12.0, 6.5 Hz, 1H, HC4), 2.37-2.33 (m, 2H,
HAC12, HBC12), 2.01-1.95 (m, 1H, HAC6), 1.81-1.76 (m, 1H, HBC6),
1.70 (s, 3H, H3C22), 1.48 (s, 3H, H3C21), 1.41 (d, J = 6.5 Hz, 3H,
H3C25), 1.37 (s, 3H, H3C19), 1.05 (s, 9H, SiR), 1.00 (d, J = 6.5 Hz, 3H,
H3C20), 0.95 (s, 9H, SiR), 0.86 (s, 9H, SiR), 0.11 (s, 3H, SiR), 0.10 (s,
3H, SiR), 0.05 (s, 3H, SiR), 0.02 (s, 3H, SiR) ppm; 13C{1H} NMR
(125 MHz, CDCl3): δ = 204.3 (C3=O), 173.9 (C1=O), 173.8 (C23=O),
137.4 (C16), 137.3 (C9H), 136.0 (SiR), 135.9 (SiR), 134.4 (C15H),
134.0 (C10), 133.8 (SiR), 132.6 (C14H), 129.8 (SiR), 129.3 (C11H),
128.3 (C8H), 127.7 (SiR), 127.6 (SiR), 126.3 (C17H), 77.1 (C5H), 76.1
(C13H), 70.7 (C7H), 70.2 (C24H), 59.3 (C2), 48.2 (C18H), 44.3 (C4H),
42.1 (C6H2), 36.8 (C12H2), 27.1 (SiR), 26.0 (SiR), 25.9 (SiR), 22.8
(C19H3), 22.3 (C25H3), 19.3 (SiR), 18.3 (SiR), 18.2 (SiR), 13.3 (C21H3),
12.8 (C22H3), 9.7 (C20H3), -4.0 (SiR), -4.5 (SiR), -4.7 (SiR), -5.0 (SiR)
ppm; IR (thin film): vmax = 3407, 2956, 2929, 2890, 2857, 1746, 1718,
Long-chain dihydropyridine 58. TLC (petroleum ether / ethyl
acetate = 4:1 v/v, KMnO ): R = 0.59; []2D4 = +152.4 (c = 0.99 in
4
f
1
CHCl3); H NMR (400 MHz, CDCl3): δ = 7.67-7.63 (m, 4H, H-Ar),
7.40-7.32 (m, 6H, H-Ar), 6.82 (d, J = 7.6 Hz, 1H, HC18), 6.04 (d, J =
15.6 Hz, 1H, HC9), 5.41 (br d, J = 4.4 Hz, 1H, HC15), 5.36 (dd, J =
15.6, 7.6 Hz, 1H, HC8), 5.27 (t, J = 7.2 Hz, 1H, HC11), 5.09 (d, J = 7.6
Hz, 1H, HC17), 4.90 (br t, J = 4.4 Hz, 1H, HC14), 4.53 (q, J = 6.8 Hz,
1H, HC24), 4.47 (m, 1H, HC7), 4.30 (t, J = 9.8 Hz, 1H, HC5), 4.01 (m,
1H, HC13), 3.62 (q, J = 6.4 Hz, 1H, HC2), 2.34 (dq, J = 10.4, 7.2 Hz,
1H, HC4), 2.23 (m, 1H, HAC12), 2.03-1.96 (m, 2H, HAC6, HBC12), 1.87
(dd, J = 8.8, 2.0 Hz, 1H, HBC6), 1.75 (s, 3H, H3C22), 1.44 (s, 3H,
H3C21), 1.37 (d, J = 6.8 Hz, 3H, H3C25), 1.32 (d, J = 6.8 Hz, 3H,
H3C19), 1.14 (d, J = 7.2 Hz, 3H, H3C20), 0.98 (s, 9H, SiR), 0.87 (s, 9H,
ACS Paragon Plus Environment

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SiR), 0.86 (s, 9H, SiR), 0.05 (s, 3H, SiR), 0.04 (s, 3H, SiR), 0.02 (s, 3H,
reaction mixture was cooled to −20 C and quenched by adding
SiR), 0.02 (s, 3H, SiR) ppm; 13C{1H} NMR (125 MHz, CDCl3): δ =
204.8 (C3=O), 172.4 (C23=O), 169.8 (C1=O), 136.3 (C9H), 136.0 (2
peaks, SiR), 134.9 (SiR), 134.1 (2 peaks, SiR, C10), 131.1 (C16), 129.7
(SiR), 129.6 (SiR), 129.1 (C11H), 128.4 (C8H), 127.7 (SiR), 127.5
(SiR), 125.8 (C18H), 116.2 (C15H), 110.4 (C17H), 76.7 (C5H), 75.9
(C13H), 71.0 (C24H), 70.7 (C7H), 54.8 (C14H), 50.4 (C2H), 46.7 (C4H),
41.4 (C6H2), 32.7 (C12H2), 27.0 (SiR), 26.0 (SiR), 25.9 (SiR), 21.2
(C25H3), 20.7 (C22H3), 19.6 (SiR), 18.3 (2 peaks, SiR), 12.8 (C21H3),
12.5 (C20H3), 8.1 (C19H3), -3.9 (SiR), -4.6 (SiR), -4.8 (2 peaks, SiR)
ppm; IR (thin film): vmax = 2955, 2930, 2894, 2857, 1764, 1724, 1659,
1590, 1471, 1462, 1428, 1390, 1376, 1361, 1258, 1111, 1089, 1005,
969, 836, 778, 740, 703, 611, 506 cm-1; HRMS-ESI (m/z): calcd. for
C53H81O7NNaSi3 [M + Na]+: 950.5213, found: 950.5195.
saturated NaHCO3 (aq., 40 mL). The resultant slurry was warmed to
room temperature and extracted with EtOAc (3 x 30 mL). The
combined organic layers were dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (petroleum ether/EtOAc: 4/1) to afford allylic
alcohol 65 (54 mg, 94% yield) as a colorless oil. TLC (petroleum
1
2
3
4
5
6
7
8
ether / ethyl acetate = 1:1 v/v, KMnO ): R = 0.36; []2D9 = −279.6 (c =
4
f
1
0.18 in CHCl3); H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 10.0
Hz, 1H), 7.68-7.60 (m, 4H), 7.41-7.28 (m, 6H), 6.01 (d, J = 15.6 Hz,
1H), 5.73 (dd, J = 15.6, 9.6 Hz, 1H), 5.53 (dd, J = 16.0, 8.4 Hz, 1H),
5.48 (t, J = 10.4 Hz, 1H), 5.24 (d, J = 16.0 Hz, 1H), 5.04 (dd, J = 11.6,
4.8 Hz, 1H), 4.51 (d, J = 10.8 Hz, 1H), 4.36 (dt, J = 12.0, 2.8 Hz, 1H),
4.26 (m, 1H), 4.20 (q, J = 6.8 Hz, 1H), 3.97 (m, 1H), 2.48 (m, 1H),
2.34-2.17 (m, 4H), 1.84 (d, J = 0.8 Hz, 3H), 1.52 (s, 3H), 1.40 (d, J =
6.8 Hz, 3H), 1.36 (s, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.04 (s, 9H), 0.95
(s, 9H), 0.11 (s, 3H), 0.09 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ = 210.8, 174.2, 170.3, 139.0, 138.6, 136.2, 136.0, 135.9,
134.4, 134.0, 133.7, 131.5, 129.7 (2 peaks), 129.1, 129.0, 127.7, 127.5,
124.6, 77.4, 76.2, 75.6, 70.3, 70.2, 57.1, 50.9, 46.4, 37.9, 36.8, 27.0,
25.9, 22.3, 20.9, 19.3, 18.2, 12.9, 12.8, 9.7, -4.6, -5.1 ppm; IR (thin
film): vmax = 3406, 2930, 2857, 1751, 1708, 1669, 1506, 1376, 1257,
1111, 1068, 963, 832, 737, 702 cm-1; HRMS-DART (m/z): calcd. for
C47H68O7NSi2 [M + H]+: 814.4529, found: 814.4505.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of lankacyclinol (5) via desilylation of 36a. Detailed
protocols leading to 5 (white solid, 20 mg, 69% yield) have been
reported previously.17 Crystals of lankacyclinol suitable for X-ray
analysis were grown by slow evaporation at 5 C from methanol. In
order to make a comparison of our synthetic lankacyclinol with
Wang’s recently isolated sample,57 NMR spectroscopic data were
recollected on this natural product using methanol-d4 as a solvent.
TLC (chloroform / methanol = 10:1 v/v, KMnO ): R = 0.25; []2D3
=
4
f
1
−353.6 (c = 0.41 in EtOH); H NMR (400 MHz, CD3OD): δ = 6.56
(m, 1H, HC5), 6.04 (d, J = 15.5 Hz, 1H, HC9), 5.74 (d, J = 15.9 Hz,
1H, HC15), 5.35 (dd, J = 15.3, 8.2 Hz, 1H, HC8), 5.31 (dd, J = 15.9,
8.0 Hz, 1H, HC14), 5.21 (m, 1H, HC11), 5.13 (t, J = 10.2 Hz, 1H,
HC17), 5.08 (t, J = 10.1 Hz, 1H, HC18), 4.25 (m, 1H, HC7), 4.11-4.04
(m, 2H, HC24, HC13), 3.64 (dq, J = 9.9, 7.0 Hz, 1H, HC2), 2.66-2.56
(m, 2H, HAC6, HBC6), 2.40 (m, 1H, HAC12), 2.27 (m, 1H, HBC12), 1.73
(s, 3H, H3C20), 1.67 (s, 3H, H3C22), 1.53 (s, 3H, H3C21), 1.35 (d, J =
6.8 Hz, 3H, H3C25), 0.97 (d, J = 6.8 Hz, 3H, H3C19) ppm; 13C{1H}
NMR (100 MHz, CD3OD): δ = 205.3 (C3=O), 177.2 (C23=O), 139.6
(C4), 139.1 (C5H), 137.9 (C9H), 136.7 (C15H), 135.4 (C10), 135.3 (C16),
131.4 (C17H), 131.3 (C14H), 129.8 (C11H), 129.3 (C8H), 75.2 (C13H),
73.4 (C7H), 69.3 (C24H), 50.3 (C18H), 44.3 (C2H), 38.5 (C6H2), 37.3
(C12H2), 21.5 (C25H3), 16.3 (C19H3), 13.1 (C21H3), 12.7 (2 peaks,
C20H3, C22H3) ppm. IR (thin film): vmax = 3327, 2920, 1656, 1639,
1545, 1452, 1370, 1264, 1129, 1017, 959 cm-1; HRMS-DART (m/z):
calcd. for C24H36O5N [M + H]+: 418.2588, found: 418.2582.
Synthesis of allylic acetate 66. To a solution of allylic alcohol 65
(30.0 mg, 0.037 mmol, 1.0 equiv) and DMAP (2.3 mg, 0.018 mmol,
0.5 equiv) in CH2Cl2 (1.5 mL) was added dropwise in sequence via
syringe Et3N (28.5 mg, 40 L, 0.276 mmol, 7.5 equiv) and Ac2O
(19.3 mg, 18 L, 0.185 mmol, 5.0 equiv). The reaction mixture was
stirred at room temperature for 20 min and then quenched by adding
saturated NaHCO3 (aq., 15 mL). The biphasic mixture was extracted
with CH2Cl2 (3 x 15 mL) and the organic layers were combined, dried
over Na2SO4 and filtered. The filtrate was concentrated under reduced
pressure. The residue obtained was purified by silica gel
chromatography (petroleum ether/EtOAc: 5/1) to provide 66 (29.3 mg,
93% yield) as a white solid. A single crystal suitable for X-ray
diffraction analysis was obtained by slow evaporation of a solution of
66 in CH2Cl2/petroleum ether at room temperature. TLC (petroleum
ether / ethyl acetate = 1:1 v/v, KMnO ): R = 0.79; []2D9= −138.1 (c =
4
f
Synthesis of lankacidinol (3) via desilylation of 36a. Detailed
procedures leading to 3 (white solid, 26 mg, 51% yield) have been
reported previously.17 In order to make a comparison of our synthetic
lankacidinol with Wang’s recently isolated sample,5,57 NMR
spectroscopic data were recollected on this natural product using
DMSO-d6 as a solvent. TLC (chloroform / methanol = 10:1 v/v,
1
0.97 in CHCl3); H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 10.4
Hz, 1H), 7.67-7.60 (m, 4H), 7.40-7.28 (m, 6H), 6.13 (d, J = 15.6 Hz,
1H), 5.64 (dd, J = 15.6, 9.6 Hz, 1H), 5.53 (dd, J = 15.6, 8.0 Hz, 1H),
5.48 (t, J = 10.4 Hz, 1H), 5.36 (ddd, J = 11.0, 10.2, 5.6 Hz, 1H), 5.26
(d, J = 15.6 Hz, 1H), 5.07 (dd, J = 11.6, 5.2 Hz, 1H), 4.52 (d, J = 10.8
Hz, 1H), 4.34 (m, 1H), 4.20 (q, J = 6.8 Hz, 1H), 3.98 (ddd, J = 10.8,
8.6, 4.0 Hz, 1H), 2.46 (m, 1H), 2.33 (m, 1H), 2.28-2.18 (m, 3H), 2.00
(s, 3H), 1.84 (s, 3H), 1.51 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H), 1.36 (s,
3H), 1.24 (d, J = 6.8 Hz, 3H), 1.04 (s, 9H), 0.95 (s, 9H), 0.11 (s, 3H),
0.09 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 210.4, 174.1,
170.3, 170.2, 141.3, 139.0, 136.0, 135.9 (2 peaks), 134.3, 134.0, 133.6,
131.5, 130.1, 129.7 (2 peaks), 127.7, 127.5, 124.6, 124.2, 76.1, 75.4,
71.8, 70.3, 57.1, 51.0, 46.4, 37.9, 34.4, 27.1, 25.9, 22.3, 21.5, 20.9,
19.3, 18.2, 12.9, 12.6, 9.5, -4.6, -5.1 ppm; IR (thin film): vmax = 3412,
2957, 2930, 2898, 2857, 1754, 1734, 1711, 1681, 1506, 1472, 1458,
1364, 1314, 1257, 1240, 1112, 1077, 1015, 963, 859, 796, 703 cm-1;
HRMS-DART (m/z): calcd. for C49H70O8NSi2 [M + H]+: 856.4634,
found: 856.4631.
KMnO ): R = 0.18; []2D3 = −215.4 (c = 0.06 in DMF); 1H NMR (400
4
f
MHz, DMSO-d6): δ = 7.77 (d, J = 10.2 Hz, 1H, H-N), 6.10 (d, J =
15.4 Hz, 1H, HC9), 5.86 (d, J = 4.7 Hz, 1H, HO-C24), 5.55 (d, J = 15.7
Hz, 1H, HC15), 5.50 (dd, J = 15.4, 9.4 Hz, 1H, HC8), 5.36 (dd, J =
15.8, 8.1 Hz, 1H, HC14), 5.32-5.24 (m, 2H, HC11, HC18), 5.04 (d, J =
4.1 Hz, 1H, HO-C13), 4.84 (d, J = 4.2 Hz, 1H, HO-C7), 4.73 (d, J =
10.7 Hz, 1H, HC17), 4.68 (m, 1H, HC5), 4.16 (m, 1H, HC7), 3.95 (m,
1H, HC24), 3.88 (m, 1H, HC13), 2.40 (m, 1H, HC4), 2.22 (m, 2H,
HAC12, HBC12), 2.11 (m, 1H, HAC6), 1.95 (m, 1H, HBC6), 1.70 (s, 3H,
H3C22), 1.41 (s, 3H, H3C21), 1.26 (s, 3H, H3C19), 1.24 (d, J = 6.7 Hz,
3H, H3C25), 1.13 (d, J = 6.6 Hz, 3H, H3C20) ppm; 13C{1H} NMR (100
MHz, DMSO-d6): δ = 211.2 (C3=O), 173.8 (C23=O), 170.5 (C1=O),
136.9 (C16), 136.0 (C9H), 135.2 (C10), 132.8 (C15H), 132.1 (C14H),
130.4 (C8H), 127.7 (C11H), 125.2 (C17H), 75.0 (C5H), 73.0 (C13H),
68.0 (C7H), 67.3 (C24H), 56.4 (C2), 50.0 (C18H), 45.9 (C4H), 37.3 (2
peaks, C6H2, C12H2), 21.2 (C25H3), 20.1 (C19H3), 12.4 (C22H3), 12.3
(C21H3), 9.2 (C20H3) ppm; IR (thin film): vmax = 3438, 3311, 2900,
1733, 1703, 1641, 1440, 1366, 1274, 1120, 1013, 960 cm-1; HRMS-
DART (m/z): calcd. for C25H36O7N [M + H]+: 462.2486, found:
462.2487.
Synthesis of lankacyclinol A (6). A mixture of allylic acetate 66
(8.6 mg, 0.01 mmol, 1.0 equiv) and H2O (7.2 mg, 0.40 mmol, 40.0
equiv) in DMF (2.5 mL) was treated with TASF (42.2 mg, 0.15 mmol,
15.0 equiv). The resultant solution was stirred for 23 hours at room
temperature, diluted with EtOAc (10 mL) and cooled to 0 C, during
which time a mixture of brine (10 mL) and phosphate buffer (aq., pH
= 7, 10 mL) was added to quench the reaction. The resultant slurry
was extracted with EtOAc (3 x 20 mL). The organic layers were
combined, washed with brine (20 mL) and dried over Na2SO4. After
filtration and concentration under vacuum, the crude product was
Synthesis of allylic alcohol 65. Hydrochloric acid (approximately
4 M in water, 2.5 mL) was added to a solution of macrocycle 36a (65
mg, 0.07 mmol) in THF (40 mL) at 20 C. After stirring for 3 h, the
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The Journal of Organic Chemistry
subjected to flash column chromatography on silica (CHCl3/MeOH:
9/1) to afford lankacyclinol A (3.6 mg, 79% yield) as a white solid.
yield) as a colorless oil. TLC (petroleum ether / ethyl acetate = 1:1
v/v, KMnO ): R = 0.27; []2D3 = −245.5 (c = 0.21 in CHCl3); 1H NMR
1
2
3
4
5
6
7
8
4
f
TLC (dichloromethane / methanol = 9:1 v/v, KMnO4): Rf = 0.46; []
(400 MHz, CDCl3): δ = 7.67-7.60 (m, 4H), 7.48 (d, J = 10.0 Hz, 1H),
7.43-7.31 (m, 6H), 6.14 (d, J = 15.2 Hz, 1H), 5.63 (dd, J = 15.6, 10.0
Hz, 1H), 5.57 (dd, J = 15.6, 8.6 Hz, 1H), 5.51 (t, J = 10.4 Hz, 1H),
5.36 (ddd, J = 10.8, 10.0, 5.4 Hz, 1H), 5.27 (d, J = 15.6 Hz, 1H), 5.07
(dd, J = 11.6, 5.2 Hz, 1H), 4.54 (d, J = 10.8 Hz, 1H), 4.36 (m, 1H),
4.25 (m, 1H), 3.99 (m, 1H), 2.46 (m, 1H), 2.34 (m, 1H), 2.31-2.17 (m,
3H), 2.01 (s, 3H), 1.84 (s, 3H), 1.51 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H),
1.38 (s, 3H), 1.25 (d, J = 6.8 Hz, 3H), 1.04 (s, 9H) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ = 211.4, 173.7, 170.3, 170.0, 141.3,
139.3, 136.0, 135.9 (2 peaks), 134.3, 134.0, 133.4, 131.9, 130.2, 129.8,
129.7, 127.7, 127.6, 124.2, 76.0, 75.4, 71.8, 68.6, 57.1, 51.3, 46.6,
37.9, 34.3, 27.1, 21.7, 21.5, 21.1, 19.3, 13.0, 12.6, 9.5 ppm; IR (thin
film): vmax = 3395, 2961, 2929, 2857, 1754, 1735, 1710, 1659, 1512,
1454, 1428, 1365, 1313, 1260, 1239, 1111, 1075, 1016, 963, 821, 798,
741, 704, 613, 507 cm-1; HRMS-ESI (m/z): calcd. for
C43H55O8NNaSi [M + Na]+: 764.3589, found: 764.3590.
24
D
1
= −180.0 (c = 0.09 in CH2Cl2/CH3OH, 1/3, v/v); H NMR (400
MHz, DMSO-d6): δ = 7.62 (d, J = 9.6 Hz, 1H, H-N), 6.48 (dd, J =
10.2, 5.2 Hz, 1H, HC5), 6.05 (dt, J = 14.8, 4.2 Hz, 1H, HC8), 5.59 (d,
J = 4.8 Hz, 1H, HO-C24), 5.57 (d, J = 16.0 Hz, 1H, HC15), 5.34-5.28
(m, 2H, HC7, HC9), 5.25-5.20 (m, 2H, HC11, HC14), 5.13 (d, J = 10.0
Hz, 1H, HC17), 4.99 (d, J = 4.4 Hz, 1H, HO-C13), 4.83 (app q, J = 10.0
Hz, 1H, HC18), 3.98 (m, 1H, HC13), 3.92 (m, 1H, HC24), 3.59 (dq, J =
10.2, 6.8 Hz, 1H, HC2), 2.68 (m, 1H, HAC6), 2.58 (m, 1H, HBC6), 2.33
(m, 1H, HAC12), 2.13 (m, 1H, HBC12), 2.02 (s, 3H, H3C27), 1.67 (s, 3H,
H3C20), 1.52 (s, 3H, H3C22), 1.45 (s, 3H, H3C21), 1.21 (d, J = 6.8 Hz,
3H, H3C25), 0.84 (d, J = 6.4 Hz, 3H, H3C19) ppm; 13C{1H} NMR (100
MHz, DMSO-d6): δ = 203.3 (C3=O), 173.7 (C23=O), 169.6 (C26=O),
138.6 (C8H), 138.5 (C4), 136.0 (C10), 134.1 (C15H), 132.9 (C11H),
132.3 (C16), 131.0 (C14H), 130.7 (C17H), 130.6 (C10), 123.2 (C9H),
73.3 (C7H), 72.5 (C13H), 67.5 (C24H), 48.2 (C18H), 42.3 (C2H), 36.6
(C12H2), 33.6 (C6H2), 21.4 (C25H3), 21.1 (C27H3), 15.6 (C19H3), 12.5
(C21H3), 12.2 (2 peaks, C20H3, C22H3) ppm; IR (thin film): vmax = 3333,
2922, 2852, 1725, 1652, 1635, 1552, 1455, 1372, 1306, 1259, 1230,
1129, 1049, 1020, 957, 879, 797 cm-1; HRMS-DART (m/z): calcd.
for C26H38O6N [M + H]+: 460.2694, found: 460.2693.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of pyruvamide 68. A suspension of 67 (16.3 mg, 0.022
mmol, 1.0 equiv, azeotropically dried with benzene) and NaHCO3
(18.9 mg, 0.22 mmol, 10.0 equiv) in dry CH2Cl2 (2.0 mL) was added
Dess-Martin Periodinane (29.5 mg, 0.066 mmol, 3.0 equiv) in one
portion. The mixture was vigorously stirred for 10 min at room
temperature until complete consumption of starting material was
indicated by TLC. The reaction was quenched with saturated NaHCO3
(aq., 15 mL) and partitioned between CH2Cl2 (30 mL) and H2O (10
mL). The organic layer was collected and the aqueous phase was
extracted with CH2Cl2 (20 mL). The combined organic extract was
dried over Na2SO4 and concentrated in vacuo. The resultant residue
was purified by preparative TLC (petroleum ether/EtOAc: 3/1) to
afford ketoamide 68 (13.1 mg, 80% yield) as a colorless oil. TLC
Synthesis of lankacidinol A (4). To a stirred solution of acetic
acid (120 mg, 120 L, 2.0 mmol) in THF (3.0 mL) at room
temperature was added TBAF (1.0 mol/L in THF, 1.0 mL, 1.0 mmol).
After stirring for 10 min, 2.4 mL of the reagent prepared as described
above was added to a solution of 66 (17.0 mg, 0.02 mmol) in THF
(2.0 mL). The resulting reaction mixture was stirred at room
temperature for 48 hours and monitored by TLC. Upon complete
desilylation, reaction quench was performed by cannulation of the
reaction mixture into a vigorously stirred, cold saturated NaHCO3 (aq.,
40 mL). The layers were separated and the aqueous layer was
extracted with EtOAc (3 x 15 mL). The combined organic layers were
washed with brine (30 mL), dried over Na2SO4, filtered and
concentrated. The resultant crude residue was purified by preparative
TLC (CH2Cl2/MeOH, 9/1) to give lankacidinol A (4, 8.3 mg, 82%
yield) as a white solid. TLC (chloroform / methanol = 10:1 v/v,
(petroleum ether / ethyl acetate = 1:1 v/v, KMnO ): R = 0.79; []2D4
=
4
f
−178.9 (c = 0.69 in CHCl3); 1H NMR (400 MHz, CDCl3): δ = 8.03 (d,
J = 10.0 Hz, 1H), 7.66-7.59 (m, 4H), 7.43-7.30 (m, 6H), 6.14 (d, J =
15.4 Hz, 1H), 5.63 (dd, J = 15.4, 9.6 Hz, 1H), 5.58 (dd, J = 16.0, 8.4
Hz, 1H), 5.42 (t, J = 10.4 Hz, 1H), 5.36 (m, 1H), 5.27 (d, J = 16.0 Hz,
1H), 5.08 (dd, J = 11.6, 5.2 Hz, 1H), 4.55 (d, J = 10.8 Hz, 1H), 4.37
(m, 1H), 3.99 (m, 1H), 2.48 (s, 3H), 2.46 (m, 1H), 2.34 (m, 1H), 2.31-
2.17 (m, 3H), 2.01 (s, 3H), 1.86 (s, 3H), 1.51 (s, 3H), 1.36 (s, 3H),
1.26 (d, J = 6.8 Hz, 3H), 1.04 (s, 9H) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ = 210.6, 196.6, 170.2, 169.8, 159.7, 141.1, 139.7, 135.8,
135.7, 134.2, 133.9, 133.1, 132.1, 130.1, 129.7, 129.6, 127.6, 127.5,
124.1, 123.4, 75.9, 75.4, 71.6, 56.8, 51.8, 46.4, 37.8, 34.2, 27.0, 24.6,
21.4, 21.0, 19.2, 12.9, 12.5, 9.4 ppm; IR (thin film): vmax = 3392, 2965,
2930, 2857, 1753, 1731, 1711, 1689, 1503, 1428, 1360, 1241, 1111,
1070, 1015, 964, 797, 742, 704, 613, 508 cm-1; HRMS-DART (m/z):
calcd. for C43H54O8NSi [M + H]+: 740.3613, found: 740.3610.
KMnO ): R = 0.38; []2D7 = −213.1 (c = 0.29 in EtOH); 1H NMR (400
4
f
MHz, CDCl3): δ = 7.56 (d, J = 10.0 Hz, 1H, H-N), 6.26 (d, J = 15.2
Hz, 1H, HC9), 5.70 (dd, J = 15.2, 9.6 Hz, 1H, HC8), 5.59 (d, J = 15.6
Hz, 1H, HC15), 5.53 (t, J = 10.8 Hz, 1H, HC18), 5.48 (dd, J = 15.6, 8.0
Hz, 1H, HC14), 5.43 (dt, J = 10.2, 5.2 Hz, 1H, HC7), 5.35 (dd, J = 10.0,
6.7 Hz, 1H, HC11), 4.67 (d, J = 11.0 Hz, 1H, HC17), 4.40 (dt, J = 12.0,
3.2 Hz, 1H, HC5), 4.23 (qd, J = 6.6, 4.0 Hz, 1H, HC24), 4.08 (dt, J =
8.2, 6.4 Hz, 1H, HC13), 2.64 (br d, J = 4.4 Hz, 1H, H-O), 2.47-2.37 (m,
3H, HC4, HAC12, HBC12), 2.35-2.21 (m, 2H, HAC6, HBC6), 2.03 (s, 3H,
H3C27), 1.89 (d, J = 0.8 Hz, 3H, H3C22), 1.55 (s, 3H, H3C21), 1.44 (d, J
= 6.8 Hz, 3H, H3C25), 1.40 (s, 3H, H3C19), 1.30 (d, J = 6.8 Hz, 3H,
H3C20) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ = 211.4 (C3=O),
173.9 (C23=O), 170.4 (C26=O), 170.0 (C1=O), 141.2 (C9H), 139.1
(C16), 136.3 (C10), 134.9 (C15H), 131.1 (C14H), 129.8 (C11H), 125.1
(C17H), 124.6 (C8H), 75.5 (C5H), 74.7 (C13H), 71.7 (C7H), 68.6
(C24H), 57.1 (C2), 51.4 (C18H), 46.6 (C4H), 37.0 (C12H2), 34.4 (C6H2),
21.6 (C25H3), 21.5 (C27H3), 21.0 (C19H3), 13.0 (C22H3), 12.7 (C21H3),
9.6 (C20H3) ppm; IR (thin film): vmax = 3400, 3341, 2989, 2968, 2923,
2864, 1747, 1719, 1707, 1637, 1553, 1522, 1457, 1434, 1371, 1316,
1241, 1130, 1078, 1023, 958, 799 cm-1; HRMS-DART (m/z): calcd.
for C27H38O8N [M + H]+: 504.2592, found: 504.2590.
Synthesis of desilylation product 67. Hydrochloric acid
(approximately 4 M in water, 0.16 mL) was added to a solution of 66
(8.0 mg, 0.009 mmol) in THF (1.4 mL) at room temperature. After
stirring for 15 hours, the reaction mixture was carefully quenched by
dropwise addition of saturated NaHCO3 (aq., 10 mL). The resultant
slurry was diluted with H2O (5 mL) and extracted with EtOAc (3 x 15
mL). The combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The crude residue was purified by preparative
TLC (petroleum ether/EtOAc: 1/2) to give alcohol 67 (5.8 mg, 87%
Dess-Martin oxidation of undried 67 in wet CH2Cl2 at room
temperature for 1 hour resulted in only 31% yield of 68 and a
significant amount of the monoepoxide 68a was isolated in 44% yield
as a colorless oil. []2D2 = −135.0 (c = 0.12 in CHCl3); H NMR (400
1
MHz, CDCl3): δ = 7.98 (d, J = 10.0 Hz, 1H, H-N), 7.64-7.57 (m, 4H,
H-Ar), 7.41-7.30 (m, 6H, H-Ar), 6.02 (dd, J = 15.6, 8.8 Hz, 1H, HC8),
5.67 (dd, J = 15.6, 8.8 Hz, 1H, HC14), 5.47 (d, J = 15.6 Hz, 1H, HC15),
5.46 (t, J = 10.4 Hz, 1H, HC18), 5.35 (m, 1H, HC7), 5.28 (d, J = 15.6
Hz, 1H, HC9), 4.60 (d, J = 11.2 Hz, 1H, HC17), 4.34 (m, 1H, HC5),
4.12 (ddd, J = 12.0, 8.8, 3.2 Hz, 1H, HC13), 2.50 (s, 3H, H3C25), 2.49
(m, 1H, HC11), 2.30-2.21 (m, 3H, HC4, HAC6, HAC12), 2.17 (m, 1H,
HBC6), 2.01 (s, 3H, H3C27), 1.88 (s, 3H, H3C22), 1.60 (m, 1H, HBC12),
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The Journal of Organic Chemistry
Page 14 of 19
1.38 (s, 3H, H3C19), 1.25 (d, J = 6.4 Hz, 3H, H3C20), 1.21 (s, 3H,
13C{1H} NMR (125 MHz, CDCl3): δ = 211.0 (C3=O), 196.7 (C24=O),
H3C21), 1.02 (s, 9H, SiR) ppm; 13C{1H} NMR (125 MHz, CDCl3): δ =
210.3 (C3=O), 196.6 (C24=O), 170.3 (C1=O), 170.2 (C26=O), 159.9
(C23=O), 140.9 (C9H), 139.6 (C16), 136.0 (2 peaks, SiR), 135.9 (SiR),
133.9 (C14H), 132.5 (C15H), 131.3 (C8H), 130.0 (SiR), 129.9 (SiR),
127.8 (2 peaks, SiR), 127.7 (SiR), 124.4 (C17H), 75.4 (C5H), 73.1
(C13H), 69.6 (C7H), 63.3 (C11H), 58.9 (C10), 56.9 (C2), 52.4 (C18H),
46.8 (C4H), 37.3 (C12H2), 34.3 (C6H2), 27.0 (SiR), 24.7 (C25H3), 21.4
(C27H3), 21.0 (C19H3), 13.7 (C21H3), 13.6 (C22H3), 9.4 (C20H3) ppm;
IR (thin film): vmax = 3499, 3388, 2960, 2928, 2856, 1743, 1728, 1710,
1690, 1504, 1461, 1428, 1360, 1313, 1260, 1238, 1109, 1079, 1017,
966, 800, 758, 704, 613, 508 cm-1; HRMS-DART (m/z): calcd. for
C43H54O9NSi [M + H]+: 756.3562, found: 756.3548.
170.0 (C1=O), 159.9 (C23=O), 139.5 (C16), 138.4 (C9H), 136.5 (C10),
134.9 (C15H), 131.3 (C14H), 129.4 (C8H), 128.8 (C11H), 124.4 (C17H),
75.8 (C5H), 74.8 (C13H), 70.1 (C7H), 56.9 (C2), 51.9 (C18H), 46.6
(C4H), 37.0 (C12H2), 36.9 (C6H2), 24.7 (C25H3), 21.1(C19H3), 13.0
(C22H3), 12.9 (C21H3), 9.8 (C20H3) ppm; IR (thin film): vmax = 3363,
2923, 2853, 1743, 1729, 1706, 1679, 1631, 1512, 1461, 1378, 1260,
1220, 1167, 1134, 1083, 1015, 966, 873, 812 cm-1; HRMS-DART
(Negative-ion mode) (m/z): calcd. for C25H32O7N [M − H]−: 458.2184,
found: 458.2178.
1
2
3
4
5
6
7
8
Neolankacidin C (69, 2.7 mg, 49% yield) was also isolated as a
white waxy solid from the above crude product mixture. TLC
9
(dichloromethane / methanol = 10:1 v/v, KMnO ): R = 0.45; []2D0
=
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
f
Synthesis of lankacidin A (sedecamycin, 2). To a stirred solution
of acetic acid (194 mg, 0.18 mL, 3.0 mmol) in THF (4.5 mL) at room
temperature was added TBAF (1.0 mol/L in THF, 1.5 mL, 1.5 mmol).
After stirring for 10 min, 4.0 mL of the reagent prepared as described
above was added to a solution of 68 (25.0 mg, 0.034 mmol) in THF
(14.0 mL). The resulting reaction mixture was stirred at room
temperature for 56 hours. Upon completion, reaction quench was
performed by cannulation of the reaction mixture into a vigorously
stirred, cold saturated NaHCO3 (aq., 60 mL). The layers were
separated and the aqueous layer was extracted with EtOAc (3 x 30
mL). The combined organic layers were washed with brine (50 mL),
dried over Na2SO4, filtered and concentrated. The resultant crude
residue was purified by preparative TLC (petroleum ether/EtOAc: 1/1)
to give lankacidin A (2, 14.7 mg, 87% yield) as a white solid. TLC
+48.7 (c = 0.22 in EtOH); 1H NMR (500 MHz, CDCl3): δ = 7.59 (d, J
= 9.6 Hz, 1H, H-N), 6.47 (dd, J = 15.4, 11.0 Hz, 1H, HC8), 5.87 (d, J
= 11.0 Hz, 1H, HC9), 5.80 (d, J = 15.4 Hz, 1H, HC15), 5.61-5.54 (m,
2H, HC7, HC14), 5.35 (dd, J = 10.6, 9.7 Hz, 1H, HC18), 4.72 (d, J =
11.0 Hz, 1H, HC17), 4.28 (dt, J = 11.5, 3.0 Hz, 1H, HC5), 4.13 (dd, J =
11.0, 4.2 Hz, 1H, HC11), 3.91 (m, 1H, HC13), 2.70 (m, 1H, HAC6),
2.51 (m, 1H, HC4), 2.45 (s, 3H, H3C25), 2.44 (m, 1H, HBC6), 2.10 (m,
1H, HAC12), 2.02 (m, 1H, HBC12), 1.88 (s, 3H, H3C22), 1.64 (s, 3H,
H3C21), 1.41 (s, 3H, H3C19), 1.17 (d, J = 6.6 Hz, 3H, H3C20) ppm;
13C{1H} NMR (125 MHz, CDCl3): δ = 209.8 (C3=O), 196.5 (C24=O),
171.3 (C1=O), 159.8 (C23=O), 139.2 (C16), 138.5 (C10), 136.5 (C15H),
134.2 (C8H), 132.9 (C14H), 128.1 (C9H), 125.8 (C17H), 123.5 (C7H),
77.9 (C5H), 77.1 (C11H), 71.9 (C13H), 57.0 (C2), 53.3 (C18H), 46.2
(C4H), 40.9 (C12H2), 32.7 (C6H2), 24.5 (C25H3), 20.4 (C19H3), 13.0
(C22H3), 11.2 (C21H3), 9.0 (C20H3) ppm; IR (thin film): vmax = 3362,
2923, 2853, 1734, 1702, 1685, 1635, 1521, 1457, 1377, 1333, 1260,
1167, 1138, 1035, 1011, 967, 888, 832, 694, 594 cm-1; HRMS-DART
(Negative-ion mode) (m/z): calcd. for C25H32O7N [M − H]−: 458.2184,
found: 458.2201.
(petroleum ether / EtOAc = 1:1 v/v, KMnO ): R = 0.35; []2D5
=
4
f
−243.9 (c = 1.14 in EtOH); 1H NMR (400 MHz, CDCl3): δ = 8.08 (d,
J = 9.9 Hz, 1H, H-N), 6.27 (d, J = 15.4 Hz, 1H, HC9), 5.70 (dd, J =
15.4, 9.7 Hz, 1H, HC8), 5.60 (d, J = 15.8 Hz, 1H, HC15), 5.50 (dd, J =
15.8, 8.2 Hz, 1H, HC14), 5.44 (t, J = 10.2 Hz, 1H, HC18), 5.43 (m, 1H,
HC7), 5.35 (m, 1H, HC11), 4.68 (d, J = 10.8 Hz, 1H, HC17), 4.41 (dt, J
= 12.1, 3.4 Hz, 1H, HC5), 4.09 (m, 1H, HC13), 2.47 (s, 3H, H3C25),
2.44-2.39 (m, 3H, HC4, HAC12, HBC12), 2.35-2.22 (m, 2H, HAC6,
HBC6), 2.03 (s, 3H, H3C27), 1.91 (s, 3H, H3C22), 1.55 (s, 3H, H3C21),
1.39 (s, 3H, H3C19), 1.31 (d, J = 6.7 Hz, 3H, H3C20) ppm; 13C{1H}
NMR (100 MHz, CDCl3): δ = 210.8 (C3=O), 196.7 (C24=O), 170.4
(C26=O), 169.9 (C1=O), 159.8 (C23=O), 141.1 (C9H), 139.6 (C16),
136.3 (C10), 134.7 (C15H), 131.4 (C14H), 129.7 (C11H), 124.6 (C8H),
124.3 (C17H), 75.6 (C5H), 74.7 (C13H), 71.6 (C7H), 56.9 (C2), 51.9
(C18H), 46.6 (C4H), 37.0 (C12H2), 34.3 (C6H2), 24.7 (C25H3), 21.6
(C27H3), 21.1 (C19H3), 13.1 (C22H3), 12.7 (C21H3), 9.6 (C20H3) ppm;
IR (thin film): vmax = 3450, 3387, 2927, 2856, 1730, 1709, 1688,
1504, 1453, 1360, 1242, 1161, 1138, 1055, 1014, 965, 866, 825, 811,
799, 738, 675, 626, 583, 547, 534 cm-1; HRMS-DART (m/z): calcd.
for C27H36O8N [M + H]+: 502.2435, found: 502.2434.
Synthesis of isolankacidinol (10) via desilylation of 36b.. A
solution of macrocycle 36b (18.0 mg, 0.0193 mmol, 1.0 equiv) in
acetonitrile (2.0 mL) was cooled to −20 C and HF (aq., 40 wt.%, 1.6
mL) was slowly added. The resulting cloudy mixture was vigorously
stirred at the same temperature for 60 hours. The reaction was then
quenched by pouring into a vigorously stirred cold solution of
saturated aq. NaHCO3 (80 mL) and stirred at room temperature for
further 30 min before it was extracted with EtOAc (3 x 60 mL). The
organic layers were combined, dried over Na2SO4 and concentrated in
vacuo. ([Note]: 1H NMR of the crude material indicated formal [1,5]-
hydroxy migration product was not formed). The crude desilylation
product was subjected to preparative TLC (10% MeOH in CHCl3) to
afford isolankacidinol (10, 7.3 mg, 82% yield) as a white solid.
Recrystallization of the purified material in MeOH/H2O (8/1, v/v) at 5
C gave crystals suitable for X-ray diffraction. TLC (chloroform /
methanol = 10:1 v/v, KMnO ): R = 0.38; []2D5 = −189.2 (c = 0.13 in
Synthesis of lankacidin C (1). A solution of pyruvamide 68 (9.0
mg, 0.012 mmol) in acetonitrile (1.5 mL) was cooled to −20 C
followed by dropwise addition of HF (aq., 40 wt.%, 1.0 mL). The
resulting cloudy mixture was vigorously stirred at the same
temperature for 65 hours and monitored by TLC. The reaction was
quenched by carefully pouring into a vigorously stirred, cold solution
of saturated NaHCO3 (aq., 80 mL). The slurry was stirred at room
temperature for further 30 min before it was extracted with EtOAc (5
x 20 mL). The organic layers were combined and dried over Na2SO4
and concentrated under reduced pressure. Further purification by
preparative TLC (CH2Cl2/MeOH, 10/1) gave lankacidin C (1, 2.4 mg,
44% yield). TLC (dichloromethane / methanol = 10:1 v/v, KMnO4):
4
f
1
EtOH); H NMR (400 MHz, CD3OD): δ = 6.21 (d, J = 15.2 Hz, 1H,
HC9), 5.82 (d, J = 15.6 Hz, 1H, HC15), 5.57 (d, J = 10.4 Hz, 1H,
HC18), 5.43 (dd, J = 15.6, 7.6 Hz, 1H, HC14), 5.32 (m, 1H, HC11), 5.29
(m, 1H, HC8), 4.97 (d, J = 10.4 Hz, 1H, HC17), 4.35 (ddd, J = 11.2,
8.4, 4.0 Hz, 1H. HC7), 4.17 (m, 1H, HC13), 4.10 (q, J = 6.8 Hz, 1H,
HC24), 3.60 (app t, J = 10.8 Hz, 1H, HC5), 3.04 (dq, J = 10.8, 6.8 Hz,
1H, HC4), 2.47 (m, 1H, HAC12), 2.32 (m, 1H, HBC12), 2.07 (m, 1H,
HAC6), 1.84 (m, 1H, HBC6), 1.73 (s, 3H, H3C22), 1.63 (s, 3H, H3C21),
1.38 (s, 3H, H3C19), 1.37 (d, J = 6.8 Hz, 3H, H3C25), 1.01 (d, J = 6.4
Hz, 3H, H3C20) ppm; 13C{1H} NMR (100 MHz, CD3OD): δ = 206.2
(C3=O), 176.9 (C23=O), 175.0 (C1=O), 139.2 (C9H), 138.2 (C16),
136.3 (C15H), 135.0 (C10), 133.4 (C14H), 131.0 (C11H), 128.7 (C8H),
127.7 (C17H), 78.7 (C5H), 75.1 (C13H), 70.8 (C7H), 69.2 (C24H), 60.2
(C2), 49.6 (C18H), 45.1 (C4H), 41.6 (C6H2), 36.9 (C12H2), 22.8 (C19H3),
21.3 (C25H3), 13.3 (C21H3), 12.9 (C22H3), 9.7 (C20H3) ppm; IR (thin
film): vmax = 3383, 2929, 1742, 1712, 1659, 1519, 1456, 1376, 1314,
1244, 1123, 1024, 965, 877, 709 cm-1; HRMS-DART (m/z): calcd.
for C25H36O7N [M + H]+: 462.2486, found: 462.2486.
R = 0.54; []2D0 = −195.8 (c = 0.08 in EtOH); H NMR (500 MHz,
1
f
CDCl3): δ = 8.07 (d, J = 10.0 Hz, 1H, H-N), 6.14 (d, J = 15.4 Hz, 1H,
HC9), 5.80 (dd, J = 15.4, 9.5 Hz, 1H, HC8), 5.59 (d, J = 15.9 Hz, 1H,
HC15), 5.50 (dd, J = 15.9, 8.1 Hz, 1H, HC14), 5.44 (t, J = 10.5 Hz, 1H,
HC18), 5.32 (dd, J = 9.7, 7.2 Hz, 1H, HC11), 4.67 (d, J = 10.9 Hz, 1H,
HC17), 4.43 (dt, J = 9.8, 5.9 Hz, 1H, HC5), 4.33 (dt, J = 8.3, 5.5 Hz,
1H, HC7), 2.47 (s, 3H, H3C25), 2.46 (m, 1H, HAC6), 2.44-2.37 (m, 3H,
HC4, HAC12, HBC12), 2.28 (m, 1H, HBC6), 1.91 (s, 3H, H3C22), 1.56 (s,
3H, H3C21), 1.39 (s, 3H, H3C19), 1.26 (d, J = 6.8 Hz, 3H, H3C20) ppm;
Decarboxylation of isolankacidinol (10) following Harada’s
protocol. To a solution of 10 (20.0 mg, 0.044 mmol) in methanol (1.0
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The Journal of Organic Chemistry
mL) was added aq. K2CO3 (2 wt.%, 1.0 mL) at room temperature. The
CH2Cl2 (0.3 mL) was treated successively with Et3N (9.0 µL, 65 µmol,
12.3 equiv), DMAP (0.7 mg, 5.7 µmol, 1.1 equiv) and 4-
bromobenzoyl chloride (11.7 mg, 53 µmol, 10.0 equiv). The reaction
mixture was stirred at room temperature for 13 hours before
partitioned between CH2Cl2 (10 mL) and H2O (10 mL). Layers were
separated and the aqueous phase was extracted with CH2Cl2 (2 x 10
mL). The combined organic extracts were dried over Na2SO4, filtered
and concentrated under reduced pressure. The oily residue was
purified by preparative TLC (petroleum ether/EtOAc: 2/1) to produce
74 (4.5 mg, quant.) as a white solid. A single crystal suitable for X-
ray analysis was obtained by slow evaporation at room temperature
reaction mixture was vigorously stirred for 1 hour at the same
temperature before acidified to pH = 2 by slow dropwise addition of 1
M HCl (aq.). The mixture was then diluted with EtOAc (30 mL) and
brine (30 mL). The layers were separated, the aqueous layer was
extracted with additional EtOAc (2 x 20 mL) and the combined
organic extracts were dried over Na2SO4 and concentrated in vacuo.
The residue was applied to preparative TLC (CH2Cl2/MeOH, 10/1) to
give lankacyclinol (5, 12.4 mg, 67% yield) and 2-epi-lankacyclinol
(62, 2.2 mg, 12% yield). A crystal of 62 suitable for X-ray analysis
were eventually grown by slow evaporation at 5 C from methanol.
Synthesis of 2,18-bis-epi-lankacyclinol (72) via desilylation of
36c. To a solution of macrocycle 36c (35.0 mg, 0.038 mmol, 1.0
equiv) and H2O (27.0 mg, 1.510 mmol, 40.0 equiv) in DMF (9.0 mL)
was added TASF (159.0 mg, 0.565 mmol, 15.0 equiv) in one portion.
The resulting orange-colored solution was stirred for 24 hours at room
temperature, diluted with EtOAc (20 mL) and cooled to 0 C, during
which time a mixture of brine (30 mL) and phosphate buffer (aq., pH
= 7, 30 mL) was added to quench the reaction. The resultant slurry
was further extracted with additional EtOAc (3 x 40 mL). The
combined organic layers were washed with brine (2 x 40 mL), dried
over Na2SO4 and concentrated in vacuo. The residue was purified by
preparative TLC (CHCl3/MeOH, 10/1) to give 2,18-bis-epi-
lankacyclinol (72, 12.1 mg, 77% yield) as a white solid. TLC
1
2
3
4
5
6
7
8
from petroleum ether/dichloromethane. []2D5 = +50.2 (c = 0.17 in
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CHCl3); H NMR (600 MHz, CDCl3): δ = 7.96 (d, J = 7.8 Hz, 2H),
7.90 (dd, J = 18.6, 7.8 Hz, 4H), 7.62 (d, J = 7.8 Hz, 4H), 7.57 (d, J =
7.8 Hz, 2H), 6.49 (s, 1H), 6.17 (d, J = 15.6 Hz, 1H), 6.06 (s, 1H), 5.99
(d, J = 15.0 Hz, 1H), 5.68-5.58 (m, 3H), 5.49 (dd, J = 15.0, 7.2 Hz,
1H), 5.45-5.37 (m, 1H), 5.37-5.27 (m, 2H), 4.85-4.74 (m,1H), 3.63 (s,
1H), 2.91-2.84 (m, 1H), 2.76-2.68 (m, 1H), 2.66-2.53 (m, 2H), 1.84 (s,
3H), 1.73 (s, 3H), 1.70 (s, 3H), 1.58 (d, J = 6.6 Hz, 3H), 1.04 (d, J =
5.4 Hz, 3H), ppm. 13C{1H} NMR (150 MHz, CDCl3): δ = 203.7,
169.7, 165.1 (2 peaks), 165.0, 140.1, 138.4, 137.3, 136.7, 134.9, 134.4,
132.2, 132.0, 131.9, 131.4, 131.3, 129.4, 128.4, 128.3 (3 peaks), 125.1,
123.4, 74.3, 73.4, 71.6, 51.0, 44.1, 33.5, 31.8, 22.8, 17.9, 16.0, 13.4,
12.7 ppm; IR (thin film): vmax = 3300, 2959, 2923, 2853, 1718, 1679,
1660, 1618, 1590, 1540, 1457, 1397, 1263, 1171, 1100, 1012, 972,
847, 800, 756 cm-1; HRMS-ESI (m/z): calcd. for C45H44O8NBr3Na
[M + Na]+: 986.0509, found: 986.0516.
(chloroform / methanol = 10:1 v/v, KMnO ): R = 0.30; []2D5 = +185.7
4
f
(c = 0.10 in MeOH); 1H NMR (400 MHz, CD3OD): δ = 6.66 (m, 1H,
HC5), 6.07 (d, J = 15.6 Hz, 1H, HC9), 5.94 (d, J = 15.8 Hz, 1H, HC15),
5.54 (dd, J = 15.9, 5.7 Hz, 1H, HC14), 5.48 (dd, J = 15.6, 6.3 Hz, 1H,
HC8), 5.32 (t, J = 7.6 Hz, 1H, HC11), 5.17 (br d, J = 9.6 Hz, 1H, HC17),
4.97 (t, J = 9.9 Hz, 1H, HC18), 4.41 (m, 1H, HC7), 4.36 (m, 1H, HC13),
4.12 (q, J = 6.8 Hz, 1H, HC24), 3.57 (dq, J = 10.3, 6.8 Hz, 1H, HC2),
2.74 (ddd, J = 13.6, 9.4, 3.9 Hz, 1H, HAC6), 2.50-2.36 (m, 3H, HBC6,
HAC12, HBC12), 1.73 (s, 3H, H3C20), 1.70 (s, 3H, H3C22), 1.65 (s, 3H,
H3C21), 1.31 (d, J = 6.8 Hz, 3H, H3C25), 0.99 (d, J = 6.8 Hz, 3H, H3C19)
ppm; 13C{1H} NMR (100 MHz, CD3OD): δ = 206.0 (C3=O), 176.9
(C23=O), 140.0 (C4), 139.2 (C5H), 136.8 (C16), 136.5 (C9H), 136.2
(C15H), 135.2 (C10), 130.6 (C14H), 129.9 (C17H), 129.1 (C8H), 128.5
(C11H), 72.0 (C7H), 71.6 (C13H), 69.1 (C24H), 50.5 (C18H), 44.9 (C2H),
37.5 (C6H2), 35.4 (C12H2), 21.3 (C25H3), 16.2 (C19H3), 13.8 (C22H3),
13.4 (C21H3), 12.4 (C20H3) ppm. IR (thin film): vmax = 3344, 2922,
2853, 1661, 1631, 1548, 1454, 1370, 1293, 1265, 1126, 1027, 1013,
967, 877 cm-1; HRMS-DART (m/z): calcd. for C24H36O5N [M + H]+:
418.2588, found: 418.2587.
Synthesis of 2,18-bis-epi-lankacidinol (75). To a stirred solution
of acetic acid (123 mg, 120 µL, 2.0 mmol) in THF (3.0 mL) at room
temperature was added TBAF (1.0 mol/L in THF, 1.0 mL, 1.0 mmol).
After stirring for 10 min, 1.5 mL of this reagent was added to a
solution of 36c (10.2 mg, 0.011 mmol) in THF (1.5 mL). The
resulting reaction mixture was stirred at room temperature for 90
hours and partitioned between saturated NaHCO3 (aq., 40 mL) and
EtOAc (20 mL). The separated aqueous layer was extracted with
EtOAc (3 x 30 mL) and the combined organic layers were washed
with brine (20 mL), dried over Na2SO4, filtered and concentrated.
Analysis of the NMR spectra collected on crude residue indicated C7-
epimerization was not observed. Purification by preparative TLC
(CH2Cl2/MeOH: 9/1) gave 75 (3.9 mg, 76% yield) as a white waxy
solid. TLC (chloroform / methanol = 10:1 v/v, KMnO4): Rf = 0.38; []
24
D
1
= +65.7 (c = 0.33 in MeOH); H NMR (400 MHz, CD3OD): δ =
8.40 (d, J = 10.0 Hz, 1H, H-N), 6.20 (d, J = 15.6 Hz, 1H, HC9), 5.96
(d, J = 16.0 Hz, 1H, HC15), 5.73 (dd, J = 16.0, 3.2 Hz, 1H, HC14), 5.43
(dd, J = 15.6, 6.8 Hz, 1H, HC8), 5.35-5.30 (m, 2H, HC18, HC11), 5.08
(d, J = 10.4 Hz, 1H, HC17), 4.62 (m, 1H, HC13), 4.47 (td, J = 7.7, 4.2
Hz, 1H, HC7), 4.15 (q, J = 6.8 Hz, 1H, HC24), 3.84 (ddd, J = 11.9, 9.7,
2.4 Hz, 1H, HC5), 3.06 (dq, J = 12.8, 6.5 Hz, 1H, HC4), 2.53 (ddd, J =
14.0, 8.5, 3.5 Hz, 1H, HAC12), 2.38 (ddd, J = 13.9, 8.3, 3.8 Hz, 1H,
HBC12), 2.07 (ddd, J = 14.1, 9.8, 4.2 Hz, 1H, HAC6), 1.96 (ddd, J =
14.2, 8.6, 2.5 Hz, 1H, HBC6), 1.79 (s, 3H, H3C22), 1.68 (s, 3H, H3C21),
1.49 (s, 3H, H3C19), 1.30 (d, J = 6.8 Hz, 3H, H3C25), 1.09 (d, J = 6.5
Hz, 3H, H3C20) ppm; 13C{1H} NMR (100 MHz, CD3OD): δ = 211.2
(C3=O), 177.0 (C23=O), 174.4 (C1=O), 139.9 (C16), 138.0 (C9H),
136.0 (C10), 133.3 (C15H), 132.8 (C14H), 129.4 (C11H), 127.5 (C8H),
125.5 (C17H), 77.3 (C5H), 71.5 (C13H), 70.4 (C7H), 69.0 (C24H), 60.2
(C2), 53.1 (C18H), 46.5 (C4H), 41.9 (C6H2), 35.0 (C12H2), 23.3 (C19H3),
21.0 (C25H3), 13.2 (C21H3), 13.1 (C22H3), 9.0 (C20H3) ppm; IR (thin
film): vmax = 3385, 2978, 2914, 2847, 1735, 1706, 1653, 1517, 1456,
1374, 1252, 1123, 1059, 1023, 967, 877 cm-1; HRMS-DART (m/z):
calcd. for C25H36O7N [M + H]+: 462.2486, found: 462.2486.
18-epi-lankacyclinol (73, 1.4 mg, 9% yield) was also isolated as a
white waxy solid from the above crude product mixture. TLC
(chloroform / methanol = 10:1 v/v, KMnO ): R = 0.40; []2D2 = +44.2
4
f
(c = 0.10 in MeOH); 1H NMR (400 MHz, acetone-d6): δ = 8.29 (d, J
= 9.6 Hz, 1H, H-N), 6.54 (ddq, J = 9.4, 6.0, 1.2 Hz, 1H, HC5), 6.16 (d,
J = 15.6 Hz, 1H, HC9), 6.01 (d, J = 15.6 Hz, 1H, HC15), 5.61-5.55 (m,
2H, HC8, HC14), 5.40 (dd, J = 8.4, 7.0 Hz, 1H, HC11), 5.10 (d, J = 9.2
Hz, 1H, HC17), 4.89 (td, J = 9.4, 3.4 Hz, 1H, HC18), 4.74 (d, J = 4.8
Hz, 1H, HO-C24), 4.58-4.52 (m, 2H, HC13, HC7), 4.15 (qd, J = 6.8, 5.2
Hz, 1H, HC24), 3.96 (d, J = 4.8 Hz, 1H, HO-C7), 3.80 (d, J = 4.8 Hz,
1H, HO-C13), 3.49 (qd, J = 7.2, 3.6 Hz, 1H, HC2), 2.71 (ddd, J = 14.4,
9.4, 6.8 Hz, 1H, HAC6), 2.54 (m, 1H, HBC6), 2.49-2.36 (m, 2H, HAC12,
HBC12), 1.80 (s, 3H, H3C20), 1.79 (s, 3H, H3C22), 1.62 (s, 3H, H3C21),
1.29 (d, J = 6.8 Hz, 3H, H3C25), 1.04 (d, J = 7.2 Hz, 3H, H3C19) ppm;
13C{1H} NMR (100 MHz, acetone-d6): δ = 208.0 (C3=O), 174.5
(C23=O), 139.7 (C4), 139.5 (C5H), 135.1 (C10), 135.0 (C9H), 134.7
(C16), 133.3 (C15H), 131.3 (C14H), 130.9 (C17H), 128.6 (C8H), 127.9
(C11H), 71.1 (C7H), 70.8 (C13H), 68.8 (C24H), 50.4 (C18H), 42.6 (C2H),
37.6 (C6H2), 35.5 (C12H2), 21.5 (C25H3), 16.4 (C19H3), 13.1 (C21H3),
12.8 (C22H3), 12.3 (C20H3) ppm; IR (thin film): vmax = 3361, 3201,
2963, 2923, 2853, 1657, 1631, 1519, 1467, 1457, 1377, 1316, 1300,
1261, 1123, 1061, 1028, 967, 871, 806, 722 cm-1; HRMS-DART
(m/z): calcd. for C24H36O5N [M + H]+: 418.2588, found: 418.2588.
Synthesis of tris-(4-bromobenzyl ester) derivative 74. A solution
of 2,18-bis-epi-lankacyclinol 72 (2.2 mg, 5.3 µmol, 1.0 equiv) in
Synthesis of 2,7,18-tri-epi-lankacidinol (76) via HF-promoted
desilylation of 36c. To a solution of macrocycle 36c (15.0 mg, 0.0161
mmol, 1.0 equiv) in acetonitrile (1.8 mL) was added HF (aq., 40 wt.%,
1.4 mL) at −20 C. The resulting cloudy mixture was vigorously
stirred at the same temperature for 96 hours until complete
desilylation of the starting material was achieved as monitored by
TLC analysis. The reaction was quenched by pouring into a
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vigorously stirred cold solution of saturated NaHCO3 (aq., 40 mL).
21. Mitteilung, Lankamycin und Lankacidin. Helv. Chim. Acta 1960,
43, 601–606.
The mixture was stirred for further 30 min and extracted with EtOAc
(3 x 25 mL). The organic extracts were combined, dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude product
was further purified by preparative TLC (5% MeOH in CHCl3, twice
development was necessary) to give 75 (4.1 mg, 55% yield) and a
slightly polar component 2,7,18-tri-epi-lankacidinol (76, 2.2 mg, 30%
yield) as a colorless oil. TLC (chloroform / methanol = 10:1 v/v,
1
2
3
4
5
6
(2) (a) Sakamoto, J. M. J.; Kondo, S.; Yumoto, H.; Arishima, M.
Bundlins A and B, Two Antibiotics Produced by Streptomyces
griseofuscus nov. sp. J. Antibiot. 1962, 15, 98–102. (b) Harada, S.;
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Bundlin A and B. Agr. Biol. Chem. 1971, 35, 27–32.
KMnO ): R = 0.37; []2D4 = +169.8 (c = 0.11 in MeOH); H NMR
1
4
f
7
8
9
(500 MHz, CD3OD): δ = 6.18 (d, J = 15.5 Hz, 1H, HC9), 5.97 (d, J =
16.5 Hz, 1H, HC15), 5.69 (dd, J = 15.5, 3.5 Hz, 1H, HC14), 5.56 (dd, J
= 11.5, 5.0 Hz, 1H, HC11), 5.48 (dd, J = 15.5, 9.5 Hz, 1H, HC8), 5.30
(d, J = 10.5 Hz, 1H, HC18), 5.07 (d, J = 10.5 Hz, 1H, HC17), 4.62 (m,
1H, HC13), 4.14 (q, J = 7.0 Hz, 1H, HC24), 4.05 (td, J = 10.3, 5.8 Hz,
1H, HC7), 3.61 (m, 1H, HC5), 3.09 (dq, J = 12.8, 6.4 Hz, 1H, HC4),
2.48 (ddd, J = 13.7, 11.4, 2.5 Hz, 1H, HAC12), 2.43-2.37 (m, 2H,
HBC12, HAC6), 1.83 (ddd, J = 16.5, 10.4, 5.0 Hz, 1H, HBC6), 1.74 (s,
3H, H3C22), 1.58 (s, 3H, H3C21), 1.48 (s, 3H, H3C19), 1.29 (d, J = 7.0
Hz, 3H, H3C25), 1.13 (d, J = 6.5 Hz, 3H, H3C20) ppm; 13C{1H} NMR
(125 MHz, CD3OD): δ = 211.1 (C3=O), 177.1 (C23=O), 174.1 (C1=O),
139.5 (C16), 139.4 (C9H), 136.8 (C10), 133.3 (C15H), 133.1 (C14H),
128.8 (C11H), 128.4 (C8H), 125.5 (C17H), 77.9 (C5H), 74.0 (C7H),
71.2 (C13H), 69.0 (C24H), 59.9 (C2), 53.2 (C18H), 46.3 (C4H), 42.4
(C6H2), 34.8 (C12H2), 23.2 (C19H3), 20.9 (C25H3), 13.0 (C22H3), 12.8
(C21H3), 8.9 (C20H3) ppm; IR (thin film): vmax = 3391, 2915, 2848,
1736, 1708, 1662, 1516, 1456, 1376, 1248, 1120, 1061, 1029, 967,
877 cm-1; HRMS-DART (m/z): calcd. for C25H36O7N [M + H]+:
462.2486, found: 462.2485.
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10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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Belousoff, M.; Wekselman, I.; Zimmerman, E.; Xiong, L.-Q.;
Klepacki, D.; Arakawa, K.; Kinashi, H.; Mankin, A. S.; Yonath, A.
The Structure of Ribosome-Lankacidin Complex Reveals Ribosomal
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107, 1983–1988. (b) Belousoff, M. J.; Shapira, T.; Bashan, A.;
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A. Crystal Structure of the Synergistic Antibiotic Pair, Lankamycin
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, as well as spectroscopic and analytical
data for all new compounds (PDF)
Crystallographic data for compound 5 (CCDC: 1978830, CIF)
Crystallographic data for compound 62 (CCDC: 1978832, CIF)
Crystallographic data for compound 66 (CCDC: 1978833, CIF)
Crystallographic data for compound 10 (CCDC: 1978835, CIF)
Crystallographic data for compound 74 (CCDC: 1978836, CIF)
AUTHOR INFORMATION
Corresponding Author
rhong@sioc.ac.cn
Notes.
╨The authors declare no competing financial interests.
ACKNOWLEDGMENT
(9) (a) Yamazaki, T.; Narukawa, N.; Suenaga, I.; Takeda, K.
Sedecamycin, a 17-Membered Macrocyclic Antibiotic Active against
Treponema hyodysenteriae. Proc. 9th Int. Pig Vet. Soc. Congr.,
Barcelona, Spain. 1986, 178. (b) Hayashi, T.; Suenaga, I.; Narukawa,
N.; Yamazaki, T. In Vitro and In Vivo Activities of Sedecamycin
against Treponema hyodysenteriae. Antimicrob. Agents Chemother.
1988, 32, 458–461.
(10) Iwatsuki, M.; Otoguro, K.; Ishiyama, A.; Namatame, M.;
Nishihara-Tukashima, A.; Hashida, J.; Nakashima, T.; Masuma, R.;
Takahashi, Y.; Yamada, H.; Ōmura, S. In Vitro Antitrypanosomal
Activity of 12 Low-Molecular-Weight Antibiotics and Observations
of Structure/Activity Relationships. J. Antibiot. 2010, 63, 619–622.
(11) Pothineni, V. R.; Wagh, D.; Babar, M. M.; Inayathullah, M.;
Watts, R. E.; Kim, K.-M.; Parekh, M. B.; Gurjarpadhye, A. A.;
We are grateful for the financial support from the National
Natural Science Foundation of China (91856202), the National
Key R&D Program of China (2019YFA09005000), the Key
Research Program of Frontier Sciences (QYZDY-SSWSLH026),
and the Strategic Priority Research Program (XDB20000000) of
the Chinese Academy of Sciences. We also thank Xuebing Leng
and Yanqing Gong (SIOC) for the X-ray crystallographic
analysis.
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ACS Paragon Plus Environment

Page 19 of 19
The Journal of Organic Chemistry
TOC ARTWORK
1
2
3
4
5
6
7
8
9
Me
iPr
Lankacidin antibiotics
lankacidin C
(bundlin A, T-2636 C)
lankacidin A
I
OTBS
Me
O
TBSO
N
CHO
Me
HN
OMe
Me
O
O
O
18
(bundlin B, sedecamycin)
2-6
steps
Bu3Sn
HN
Me
4
Me
7
6 steps
lankacidinol
lankacidinol A
(T-2636 F)
(T-2636 D)
S
N
2
TBSO
5
O
O
lankacyclinol
(T-2636 G)
EtO2C
SO2
OMe
13
lankacyclinol A
(T-2636 E)
TBSO
OTBDPS
Bn
O
O
N
O
isolankacidinol
(revised)
2,18-bis-epi-lankacyclinol
O
Me
the synthetic precursor for
biomimetic Mannich macrocyclization
TBSO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
Me
Me
novel family member
(revised,
)
O
Insert Table of Contents artwork here
19
ACS Paragon Plus Environment